1. Introduction
Histone chaperones serve a pivotal role in histone metabolism, facilitating histone binding to DNA during processes such as DNA replication and repair (1). Originally, Laskey et al (2) revealed that nucleophosmin in Xenopus eggs can bind histones and promote nucleosome formation independently of ATP. These two properties remain the only shared, and thus defining, characteristics of histone chaperones. Currently, histone chaperones are deemed to aid histone transfer but remain separate from the final histone-DNA complex (3). Extensive research has been conducted on the relationship between histone chaperones and human diseases (3-5). Their abnormal expression patterns, not only in tumors, but also in cardiovascular diseases, autoimmune disorders and neurodegenerative diseases, highlight their prognostic value in various human diseases. Given their role in chromatin dynamics and disease contexts, they present potential therapeutic targets and diagnostic markers in various human diseases.
Retinoblastoma binding protein (RBBP)4 and RBBP7 are recognized as histone chaperones, both of which belong to the WD40 family (6). The WD40 domain is a distinct protein motif that typically adopts a β-propeller architecture, mediating protein-protein interactions (PPIs). RBBP4/7 typically exist in complexes, such as the nucleosome remodeling and deacetylase (NuRD) complex (7) and polycomb repressive complex 2 (PRC2) (8), to regulate chromatin remodeling and gene expression through the interactions of their WD40 repeats with the H4 α1 helix and H3 tail (9,10). Dysregulation of RBBP4/7 may disrupt the normal chromatin remodeling process, resulting in altered gene expression patterns that contribute to the initiation and progression of cancer and other human diseases (11). Notably, alterations in the expression levels of RBBP4/7 have been observed in different types of human disease, such as esophageal squamous cell carcinoma (ESCC) and colorectal cancer (CRC). These changes are closely related to clinicopathological features (12-15).
The present review summarizes the pivotal role of RBBP4/7 in regulating cell fate, assessing their expression, functions, clinical features and associated mechanisms in human diseases.
2. Molecular structure of RBBP4 and RBBP7
RBBP4, also known as RbAp48 or NURF55, is integral to multiple chromatin-modifying and remodeling complexes. It was originally discovered as a binding partner of the tumor suppressor retinoblastoma protein (RB) in yeast (16), and subsequently revealed to cofractionate with histone deacetylase (HDAC)1 (17). Located on chromosome 1p35.1, the RBBP4 gene encodes a 425-amino acid protein ubiquitously present across human tissues (18). The molecular structure of the RBBP4 protein is shown in Fig. 1A.
RBBP7, alternatively known as RbAp46, is a nuclear protein ubiquitously expressed across various cell types. Located on chromosome 3p25.1, the RBBP7 gene encodes a 425-amino acid protein that is universally expressed in human tissues (18). RBBP4 and RBBP7 are 92% identical (9); however, they differ in certain amino acid sequences, which may lead to subtle structural variations, especially in domains that interact with other proteins. The molecular structure of RBBP7 is displayed in Fig. 1B. Structurally, both RBBP4 and RBBP7 possess a seven-bladed WD40 repeat domain, indicating that RBBP4 and RBBP7 can serve multiple roles in chromatin remodeling, histone modification and transcriptional regulation (19). Notably, both RBBP4 and RBBP7 are integral subunits of the NuRD complex (7), the switch-independent 3A complex (20) and PRC2 (8). Additionally, RBBP4 has been identified as a subunit of the chromatin assembly factor 1 (CAF-1) complex (21) and a core component of the MuvB complex (22), while RBBP7 is known to be an essential component of the histone acetyltransferase 1 (HAT1) complex (23). As part of these multisubunit protein complexes, RBBP4 and RBBP7 are believed to function as chromatin adapters, mediating direct interactions with histone H3/H4 (24).
3. The biological functions of RBBP4/7
The functions of RBBP4/7 in the cell cycle
RBBP4/7 have a pivotal role in cell cycle regulation, with their absence leading to dysregulation of cell cycle genes and cycle arrest (25). Specifically, RBBP4 deficiency results in S phase defects and inhibits mitotic exit (M to G1 transition) (26), whereas RBBP7 deficiency causes G2/M phase arrest in 293 cells (27). In addition, RBBP4/7 (LIN-53) are crucial for centromere protein A (CENP-A) localization to centromeres (28). It has also been suggested that the Cullin-4 (CUL4) RING ligase (CRL4) complex containing RBBP7 might regulate mitosis by promoting ubiquitin-dependent loading of newly synthesized CENP-A during the G1 phase (29).
RBBP4/7 are members of the RB family (30). Studies conducted in yeast and cultured cells have shown that RBBP4 appears to function as a tumor suppressor along with RB, leading to inhibition of cell cycle progression and cell growth (16,18). Nevertheless, Schultz-Rogers et al (31) indicated that RBBP4 is essential for the cell cycle progression of neural progenitor cells and the initiation of G0, irrespective of the involvement of RB. The E2F family plays a key role in cell cycle regulation, and all RB family members interact with typical E2F proteins to form transcriptional inhibition complexes (32). RB primarily inhibits E2F transcription factor 1, whereas RBBP4 can be directed to RB via HDAC1 (33). In the G1 phase, RBBP4/7 and RB inhibit E2F target gene activation, preventing entry into S phase. Cyclin D-cyclin-dependent kinase (CDK)4/6 can monophosphorylate RB, whereas cyclin E-CDK1/2 are involved in poly-phosphorylation or hyper-phosphorylation of RB (34). Once hyperphosphorylated, RBBP4/7 and RB dissociate from E2F, activating target genes and recruiting chromatin remodelers (35) (Fig. 2A).
In addition, RBBP4 is a core component of the MuvB complex, collaboratively working with LIN9, LIN37, LIN52 and LIN54 to regulate the cell cycle (22). During the G0/G1 phase, the RBBP4-containing MuvB complex associates with p130/E2F4/DP1 to form the dimerization partner, RB-like, E2F and MuvB (DREAM) complex (36), which inhibits expression of cell cycle regulatory genes, maintaining the cell in a quiescent state. Within the DREAM complex, RBBP4 directly binds to LIN9 and LIN37 within the complex, playing a pivotal role in its assembly process (22). Additionally, RBBP4 collaborates with p130, E2F4 and DP1 to inhibit the transcriptional activity of E2F target genes (36). As the cell cycle progresses, phosphorylation by CDK leads to the disassembly of the DREAM complex, releasing p130/E2F4/DP1 from MuvB. Subsequently, the MuvB complex, inclusive of RBBP4, interacts with activated transcription factors B-MYB (also known as MYB proto-oncogene like 2) and forkhead box M1 (FOXM1), culminating in the formation of the activated MYB-MuvB-FOXM1 complex. This complex further regulates the expression of cell cycle genes, especially during the G2 phase and mitosis (37) (Fig. 2B). Thus, RBBP4, through its positioning and recruitment roles in the MuvB complex, serves a critical role in the regulation of various stages of cell cycle gene expression. Notably, the DREAM complex collaborates with RB during quiescence to suppress cell cycle gene expression (38,39). Furthermore, in response to the p53 tumor suppressor and genotoxic stress, the involvement of RBBP4 within the DREAM complex and its collaboration with RB becomes evident. Specifically, the DREAM complex and RB utilize the p53-p21 pathway to induce p21 and consequently arrest the cell cycle (39,40). The dual association of RBBP4 with the RB family and the DREAM complex indicates that it has a crucial role in maintaining cell cycle arrest.
Finally, RBBP4/7 serve as components of chromatin-remodeling complexes, such as NuRD and PRC2, further modulating the cell cycle via nucleosome acetylation and methylation regulation (8,41).
In summary, RBBP4/7, as components of the RB family or MuvB complex, have a pivotal role in cell cycle regulation. Their association with chromatin remodeling further influences cell cycle progression. While the role of RBBP4/7 in the cell cycle is evident, the specifics of their mechanism require further exploration.
The multifaceted role of RBBP4/7 in chromatin remodeling
Chromatin remodeling is a critical process that governs the accessibility of DNA to various cellular machineries, influencing gene transcription, replication and repair (42). RBBP4/7 can affect histone conformation by directly binding to histone H4 and H3 (43).
The NuRD complex, comprising several subunits, including the HDAC complex, chromodomain helicase DNA binding protein 3/4 ATPase, methyl-CpG binding domain protein 2/3, RBBP4/7, metastasis associated 1/2/3 (MTA1/2/3) and GATA zinc finger domain containing 2A/B, is a multifunctional entity with nucleosome remodeling and deacetylase activities (44). These activities enable the NuRD complex to alter chromatin structure, thereby regulating gene expression. Mu et al (45) suggested that RBBP4 may contribute to controlling the acetylation (ac) of lysine 27 on histone H3 (H3K27ac) levels at enhancer elements by promoting the deacetylase activity of the HDAC complex, effectively removing acetyl groups from H3K27 (Fig. 3A). RBBP4/7 also have regulatory chromatin remodeling effects independent of NuRD complexes. RBBP4 promotes H3K27ac by maintaining p300 levels (46), and together with RBBP7, mediates H4K5ac and H4K12ac to enable CENP-A deposition into centromeres (47). A network including SIN3 transcription regulator family member A-HDSAC3-RBBP4-H4 recognizes and deacetylates histones during chromatin assembly (48). RBBP4 also controls histone deacetylation at H3K4, H4K8, H4K12 and H4K16 during meiosis I (49). Additionally, RBBP4/7 collaborate with HAT1 in the site-specific de novo acetylation of histone H4 (50), facilitating its nuclear delivery and folding (51), which may be crucial in chromatin assembly and gene expression regulation.
PRC2, consisting of core subunits SUZ12 polycomb repressive complex 2 subunit (SUZ12), embryonic ectoderm development (EED), RBBP4/7 and enhancer of zeste homolog (EZH)2 or EZH1, is the sole confirmed methyltransferase responsible for the mono-, di- and trimethylation of H3K27, generating the H3K27me3 mark (52). RBBP4/7 interact with various molecules to facilitate PRC2 recruitment and activity modulation. Studies have shown that RBBP4 can recruit SUZ12 to PRC2 target sites, and methylate H3K27 or H1K26 with the histone lysine N-methyltransferase EZH2 (45,53). Simultaneously, EED can interact with the H3K27me3 mark, thereby activating the methyltransferase activity of EZH2 and influencing the overall activity of PRC2. Consequently, this process promotes the 'spreading' of H3K27me3 (54) (Fig. 3B). Notably, the absence of the SUZ12-RBBP4 complex influences H3K27me3 (55). Therefore, as pivotal constituents of PRC2, RBBP4/7 emerge as determinants of site-specific H3K27me3 and other histone methylations across the genome.
RBBP4/7 also exhibit methyltransferase activity independent of PRC2. Kitange et al (56) showed that RBBP4 knockdown can enhance the levels of H3K9 trimethylation. RBBP4/7 interact with SUV39H1 to specifically methylate lysine 9 on histone H3, leading to heterochromatin silencing or RB transcriptional repression (57). Furthermore, RBBP7 inhibits DNA methyltransferase 1, affecting DNA methylation and limiting transcription factor access to promoters (58).
In summary, RBBP4/7 serve an important role in regulating histone deacetylation and methylation, which are key processes in chromatin remodeling and the regulation of gene expression. The precise mechanisms underlying these regulatory activities of RBBP4/7 both inside and outside the aforementioned complexes remain an area of ongoing research and exploration.
The role of RBBP4/7 in the DNA damage response
RBBP4/7 have been identified as crucial components of several protein complexes involved in DNA repair, making them essential players in maintaining genome integrity.
The NuRD complex governs gene expression and DNA damage repair by modulating nucleosome RNA polymerase accessibility at transcription factor binding sites, enhancers and promoters (59). RBBP4/7, as subunits of the NuRD complex, mediate the interaction of NuRD with histone tails and transcription factors (59). Yang et al (60) showed that breast cancer (BC) anti-estrogen resistance 1 and RBBP4 can form a complex, be recruited to chromatin, and jointly occupy the promoter regions of some DNA repair genes, and promote DNA damage repair. Similarly, RBBP4/7 specifically interact with the C-terminal domain of BC type 1 susceptibility protein (BRCA1) and inhibit its transactivation activity (61). The association between BRCA1 and RBBP7 is disrupted in cells treated with DNA-damaging agents (62). Therefore, the interaction between RBBP4/7 and BRCA1 might be the key to regulating DNA damage repair.
Li et al (63) demonstrated that RBBP4 disruption results in heightened DNA damage and apoptosis in glioblastoma (GBM) cells post-temozolomide (TMZ) and radiotherapy. Additionally, in MCF10AT3B cells, which are neoplastigenic breast epithelial cells derived from a model of human proliferative breast disease, high levels of RBBP7 might induce the growth arrest- and DNA damage-induced (GADD) gene, GADD45 (64). Consequently, aberrant expression of RBBP4/7 has implications for the DNA damage repair response.
In summary, RBBP4/7 serve a pivotal role in DNA damage repair and gene regulation, particularly in collaboration with BRCA1. Their interaction with BRCA1 facilitates DNA repair, and aberrant expression may affect this response, leading to the accumulation of DNA damage, as cell cycle progression and increased carcinogenic risk (Fig. 4). The complexity of these interactions warrants further investigation.
The role of RBBP4/7 in cell development, differentiation, maturation and senescence
In mouse oocytes, RBBP4 is crucial for bipolar spindle formation, and its deficiency can lead to mitotic abnormalities (49), suggesting its importance in cell division, a fundamental process of cell growth. RBBP7 is strongly expressed in the kidneys and brain from embryonic day 9.5 (65), regulating Kisspeptin-1 expression to participate in reproductive development (66). Giri et al (67) revealed that RBBP7 can be suppressed in relation to Ras-associated cell proliferation through stabilization by small ubiquitin like modifier 1.
RBBP4 is indispensable in heterochromatin assembly and serves as a crucial barrier in inducing cell fate transition from pluripotency to totipotency. Ping et al (68) demonstrated that the deletion of RBBP4 enhances the transition of mouse embryonic stem cells to trophectoderm cells. In the NuRD complex, RBBP4/7 and MTA interact with friend of GATA protein 2 (FOG-2) and are involved in FOG-2-mediated inhibition of GATA binding protein 4 activity, preventing the aberrant cell differentiation that leads to cardiac malformations (69). Moreover, the RBBP4 homolog DjRbAp48 in planarians (Dugesia japonica) regulates stem cell differentiation (70). In addition, notable discoveries have been made in the study of RBBP7. RBBP7 is involved in regulating histone acetylation and the expression of cyclin D3 in post-implantation trophoblast matrix cells (71), and it interacts with the pregnancy-induced non-coding RNA, inhibiting the differentiation of alveolar cells during pregnancy (72). Xin et al (73) showed that RBBP4/7 may be indirectly involved in the differentiation process of bone marrow cells by affecting the expression of the long noncoding RNA HOTAIRM1. Finally, in kidney development, RBBP7, as a target gene of the transcription factor Wilms tumor 1, exhibits decreased expression, reflecting podocyte dedifferentiation (74). These data suggested that RBBP4/7 may have a key role in cell differentiation processes.
During cell growth, RBBP4 influences cell morphology and cytoskeleton organization by enhancing K-Ras activity and mitogen-activated protein kinase signaling (75). Gasca et al (76) proposed that RBBP7 is involved in the maturation of oocytes. Likewise, RBBP7 also contributes to histone deacetylation during oocyte maturation (77). By contrast, Guan et al (78) showed that RBBP7 has strong growth inhibitory activity in the developing kidney and gonads. In summary, RBBP4/7 play diverse roles in cell maturation, influencing cell morphology, oocyte maturation and organ growth.
In aging human fibroblasts, a decrease in RBBP4 expression leads to chromatin defects (79). Concurrently, Hunt et al (80) demonstrated that ubiquitin protein ligase E3 component N-recognin 4 deficiency prevents skeletal muscle cell aging and atrophy by reducing the ubiquitination and degradation of the HAT1/RBBP4/RBBP7 histone-binding complex. Additionally, decreased RBBP4 expression in the aging hippocampus is associated with memory loss (81). Tsujii et al (82) further illustrated that RBBP4 knockdown might inhibit nuclear transport and induce cellular aging. Furthermore, RBBP7 has been reported to be consistently upregulated in the lobules of degenerated mammary glands and to be associated with hormone induction (83). Collectively, RBBP4/7 are closely associated with cellular senescence, affecting chromatin defects, skeletal muscle cell aging and memory loss.
In summary, RBBP4/7 exhibit diverse functions throughout cell growth and development, impacting essential cellular processes and providing valuable insights into cellular differentiation, aging and chromatin regulation.
4. Expression and function of RBBP4/7 in diseases
Aberrant expression of RBBP4/7 has been observed in several diseases. The present review summarizes the various diseases regulated by RBBP4/7 (Fig. 5), the clinical characteristics of RBBP4 and RBBP7 in human diseases (Tables I and II), and their roles and mechanisms in disease development (Tables III and IV).
Respiratory system Lung cancer (LC)
RBBP4 is associated with genetic susceptibility to LC (84). Elevated RBBP4 expression in non-small cell LC (NSCLC) tissues amplifies cell proliferation and invasion, and is concomitantly linked to an adverse clinical outcome (13,84). RBBP4 is also increased in cisplatin-resistant NSCLC, affecting drug resistance (85), and is associated with enhanced DNA damage sensitivity and repair pathway activity (86). Additionally, in lung adenocarcinoma (LUAD) cells, RBBP4 interacts with chromobox homolog 3, which is found to be upregulated in current smokers with LUAD, thereby promoting LUAD progression (87). Thus, RBBP4 could be a potential biomarker or therapeutic target for LUAD recurrence and prognosis post-platinum treatment.
Research has revealed that the expression levels of RBBP7 in NSCLC are higher than those in normal lung tissues, and this elevated expression is associated with distant metastasis, poor prognosis and tumor immune response in NSCLC, serving as a predictor for the recurrence of early-stage NSCLC (88-90).
Despite these significant findings, the understanding of the functions of RBBP4/7 in LC is limited and more in-depth research is needed to develop new treatment strategies.
Malignant pleural mesothelioma (MPM)
MPM has an average survival of 1 year post-diagnosis, urgently necessitating improved treatment methods (91). Vavougios et al (92) showed that RBBP4/7 interact with Parkinson disease protein 7 and are upregulated in an array of 18 different sarcoma types. However, the mechanism by which RBBP4/7 functions in MPM remains unknown.
Nervous system
GBM and other brain tumors
RBBP4 plays an indispensable role in the disease development of GBM (93), with its mRNA expression universally upregulated in GBM tissues where it acts as an oncogene to promote GBM malignancy, countering the tumor-suppressive effects of microRNA (miR)-885-5p (94). In GBM cells, the RBBP4/p300 complex governs pro-survival genes and influences the responsiveness to TMZ (95). This suggests that disrupting RBBP4 or p300 might enhance sensitivity to TMZ. In addition, RBBP4 increases TMZ resistance by regulating the expression of the MRN complex (MRE11 homolog, RAD50 double-strand break repair protein, and nibrin), thereby reducing sensitivity to radiotherapy and TMZ (63). Therefore, RBBP4 potentially enhances cancer progression or drug resistance through DNA repair and might be considered a new therapeutic target for future GBM treatment.
RBBP4 is required during brain development, and RBBP4 is upregulated in RB1-mutated embryonic brain tumors, serving as a potential target for inducing apoptosis in RB1-mutated brain cancer cells (96). Additionally, in neuroblastoma, RBBP4 is upregulated and is associated with poor patient prognosis (97).
By contrast, limited research has been conducted on the involvement of RBBP7 in GBM. Notably, Crea et al (98) explored the Oncomine database and observed an upregulation of RBBP7 in anaplastic astrocytoma and anaplastic oligodendroglioma.
Age-related memory loss
Loss of RBBP4 is key to age-related memory decline. Its expression in human and mouse brains declines with age, affecting memory formation (81). Another study demonstrated that RBBP4 regulates the expression of brain-derived neurotrophic factor and G protein-coupled receptor 158, key components of the mouse hippocampal osteocalcin (OCN) signaling pathway (99). Inhibition of RBBP4 disrupts the cognitive benefits of OCN and leads to discriminative memory deficits (100). Furthermore, certain genetic variants in a cAMP element binding protein-dependent histone acetylation pathway, associated with RBBP4, influence memory performance in cognitively healthy elderly individuals (101). Therefore, RBBP4 could serve as a potential therapeutic target for age-related memory loss.
Current research has explored RBBP4/7 as therapeutic targets to address age-related memory loss. The functional role of RBBP4 in Alzheimer's disease (AD) might be influenced by the instability of the RBBP4-FOG1 complex (102). Huang et al (103) identified three traditional Chinese medicine compounds (bittersweet alkaloid ii, eicosanedioic acid and perivine), which could enhance the stability of the RBBP4-FOG1 complex, offering potential therapeutic benefits for AD. However, another study showed that RBBP4/7 did not contribute to the neuroprotective effects of green tea polyphenols (104). Thus, the mechanism of RBBP4/7 as a target for age-related memory loss requires further investigation.
Dave et al (105) discovered that RBBP7 mRNA expression is diminished in AD cases, with significant negative correlations with the Consortium to Establish a Registry for AD and Braak stage. Moreover, this previous study revealed that high RBBP7 expression mitigates tau acetylation and phosphorylation, thereby preventing tau pathologies (105).
In summary, RBBP4/7 play crucial roles in age-related memory deficits, and present promising therapeutic targets for future interventions in cognitive aging and associated diseases.
Hematological (blood and bone marrow) system diseases Acute myeloid leukemia (AML)
In AML, elevated RBBP4 expression is linked to poorer survival and disease progression (106-108). Moreover, AML primary blasts with lower levels of ring finger protein 5/RBBP4 have demonstrated increased sensitivity to the HDAC inhibitor FK228. These findings suggest that the abundance of RBBP4 may serve as valuable marker to stratify patients with AML who might benefit from treatment with HDAC inhibitors (106). However, to the best of our knowledge, there is no currently research indicating an association between RBBP7 and AML.
Multiple myeloma (MM)
Gao et al (109) showed that RBBP4 is a core gene in MM, and its dysregulation is evident in the epigenetic modifications of MM. Thus, RBBP4 emerges as a potential focal point in MM research, providing promising avenues to understand the pathogenesis of MM and develop more effective therapeutic strategies. However, to the best of our knowledge, no studies have revealed a role for RBBP7 in MM.
Chronic myeloid leukemia (CML)
CML is a malignant hematological disorder. It has been shown that BMI1 (encoding B lymphoma Mo-MLV insertion region 1 homolog) transcript levels are significantly increased in CML cells, and the expression of RBBP4 is decreased after BMI1 silencing (110). In addition, RBBP7 in K562 leukemic cells inhibits growth by inducing IGFBP7 expression (111). These findings revealed that RBBP4/7 might serve an important role in the biological process of CML. However, the expression levels of RBBP7 were significantly elevated in patients with acute leukemia and CML in blast crisis compared with healthy donors and those with CML in chronic phase, indicating that it might be involved in the occurrence of leukemia (112,113). In addition, RBBP7 overexpression slows growth in the U937 leukemia cell line (114).
Osteosarcoma
Osteosarcoma originates from primitive mesenchymal cells in the bone, rarely in soft tissue, and if untreated, can lead to local and often metastatic progression (115). Zhang et al (116) showed that the inducible expression of RBBP7 can activate the c-Jun N-terminal kinase signaling pathway, and trigger apoptosis in Saos-2 osteosarcoma cells, while also strongly suppressing the formation of tumor grafts in nude mice and significantly reducing the growth of established osteosarcoma xenografts.
Digestive system
CRC
RBBP4 has been identified as a key factor in CRC, with studies showing its upregulation in colon cancer tissues, and linking increased RBBP4 expression to poor prognosis and liver metastasis (117). Reducing RBBP4 levels can hinder the growth and migration, and increase the apoptosis of HCT116 and SW620 colon cancer cells, and also suppress the Wnt/β-catenin pathway (12). Concurrently, knocking down RBBP4 also inhibits H3K27ac acetylation and HSPB8 gene transcription (118). Another study demonstrated that RBBP4 is a key target of protopanaxadiol (PPD), a major ginseng metabolite (119), suggesting its potential as a new diagnostic and therapeutic target for CRC.
RBBP7 has been reported to form a trimeric complex with long non-coding RNA FIT and p53, enhancing p53-mediated FAS gene transcription, which promotes CRC cell apoptosis (15). This suggests the apoptosis-inducing role of RBBP7 in CRC, which differs from the role of RBBP4. However, the precise expression and mechanism of RBBP7 in CRC warrant further investigation.
Gastric cancer (GC)
Ding et al (120) revealed that the expression of RBBP4 is increased in GC tissues, and knocking down RBBP4 can significantly inhibit GC cell proliferation, migration and invasion, and promote cell apoptosis. Radiation can also increase RBBP4 expression in AGS GC cells, leading to G2 phase arrest. Moreover, RBBP4 enhances the radiosensitivity of these cells by inhibiting the PI3K/Akt pathway (121). These results underscore the potential of RBBP4 as a promising target for future gene therapy interventions in the treatment of GC.
Currently, research on the role of RBBP7 in GC is limited. Src-suppressed C-kinase substrate (SSeCKS), a crucial substrate for protein kinase C, is significantly downregulated in GC (122). Liu et al (123) demonstrated that the re-expression of SSeCKS induces RBBP7, suggesting a potential connection. However, the specific function and significance of RBBP7 in GC remains to be further determined.
Hepatocellular carcinoma (HCC)
It has been shown that RBBP4 is highly expressed in liver tumor tissues, and is associated with clinical severity and disease prognosis (124). In HCC cells, Liu et al (125) identified that RBBP4 interacts with the N-terminal peptide of Sal-like protein 4 (SALL4), contributing to the silencing of tumor suppressor genes, such as PTEN. Furthermore, a potent SALL4 peptide antagonist (FFW) targeting RBBP4 significantly inhibits HCC cell growth. These studies have shown that RBBP4 plays a role in promoting HCC, which is expected to be a potential target for future HCC treatment.
By contrast, Li et al (126) observed a decrease in RBBP4 expression in HCC tissues; it was revealed that RBBP4 knockdown may enhance the self-renewal and tumorigenic potential of epithelial cell adhesion molecule-positive liver tumor-initiating cells, suggesting that RBBP4 serves as a downstream target of miR-429. Furthermore, epigallocatechin gallate (EGCG) can reverse multidrug resistance (MDR) in HCC, and RBBP4 has been reported to be significantly upregulated after EGCG treatment (127), suggesting that RBBP4 could be a potential anti-MDR target in HCC.
Nonalcoholic fatty liver disease
Hepatic steatosis, crucial in nonalcoholic steatohepatitis development, elevates the risk of cirrhosis and HCC (128). Within the NuRF complex, the subunit RBBP4 assumes a role in the regulation of lipid droplet size by transcriptionally suppressing target genes (129). Zhi et al (130) suggested that RBBP4 exerts a favorable influence on liver cell steatosis by promoting the expression of genes associated with fatty acid β-oxidation. These findings illustrate a protective role of RBBP4 in the context of hepatic steatosis.
Esophageal cancer (EC) and hypopharyngeal carcinoma
Research has shown that RBBP4 is upregulated in ESCC and promotes the epithelial-mesenchymal transition (EMT) process (131). By contrast, Bai et al (132) demonstrated that in hypopharyngeal carcinoma, a distinct squamous cell carcinoma impacting the upper aerodigestive tract, RBBP4 overexpression curtails proliferation, colony formation and tumorigenesis in the FaDu hypopharyngeal carcinoma cell line. The role of RBBP4 in hypopharyngeal carcinoma growth appears linked to its modulation of tumor suppressors. This contrasting role of RBBP4, from facilitating tumor progression in ESCC to inhibiting growth in hypopharyngeal carcinoma, demonstrates its functional variability across different types of cancer, highlighting its potential complexity as a therapeutic target.
Yu et al (14) observed that higher RBBP7 expression in ESCC tissues is correlated with poor differentiation, advanced lymph node involvement, higher tumor-node-metastasis stage, reduced survival, and increased cell invasion and migration. Mechanistically, hypoxia can induce high expression of RBBP7, which in turn upregulates CDK4 expression and promotes tumor progression (133). Furthermore, RBBP7 is upregulated in EC. As a target of miR-384, RBBP7 mRNA levels are elevated by circ_0006168 through its interaction with miR-384. This, in turn, promotes cell proliferation, migration, invasion and glycolysis in EC (134).
Collectively, RBBP4/7 are crucial in EC progression and prognosis, with their complex molecular interactions making them promising for future therapeutic and diagnostic developments in esophageal oncology.
Endocrine system
Thyroid cancer (TC)
Pacifico et al (135) detected increased RBBP4 expression in primary human TC via immunohistochemical analysis, particularly in undifferentiated TC samples and cell lines. In addition, RBBP4 knockdown was shown to reduce FRO anaplastic thyroid carcinoma cell colony formation, suggesting RBBP4 as a target of nuclear factor (NF)-κB and a potential therapeutic target for NF-κB-dependent TC. Therefore, RBBP4 might be a potential target for TC therapy, particularly for NF-κB-dependent cases.
Postmenopausal osteoporosis (PMOP) and other estrogen-influenced conditions
PMOP represents a significant global public health concern. RBBP4 expression is elevated in estrogen-deficient rats and patients with PMOP, decreasing after treatment with Liuwei Dihuang pills (136,137). Moreover, RBBP4 has been reported to be upregulated in the blood of patients with PMOP, suggesting that it could serve as a potential diagnostic biomarker of PMOP (138). The interaction between RBBP4 and estrogen receptor 1 (ESR1) is believed to serve a crucial role in the pathogenesis of PMOP (138). In summary, RBBP4 serves as a potential biomarker for PMOP diagnosis and its interaction with ESR1 suggests a fundamental mechanism in PMOP pathogenesis.
Additionally, estrogen deficiency-induced overexpression of RBBP4 triggers p53-mediated apoptosis in exocrine cells, implying a link to autoimmune exocrine disorders in postmenopausal women (139,140). Therefore, RBBP4 represents a novel immunotherapeutic target for preventing the development of sex-based autoimmune exocrine disorders.
Reproductive system
BC
RBBP4 is highly expressed in BC and is associated with poorer overall survival and a greater likelihood of lymph node metastasis (141). Knockdown of RBBP4 inhibits the proliferation, migration and invasion of BC cells, while affecting the transcription of tumor-related genes, such as microfibril-associated protein 2, which is activated via the interaction between RBBP4 and the long noncoding RNA LCPAT1 (142). Another study showed that RBBP4/7 interact with DNA-bound estrogen receptor α to alter the expression of estrogen-responsive genes in MCF-7 cells (143). Thus, RBBP4 is implicated in BC progression, in which it influences survival, metastasis and estrogen-responsive gene expression.
RBBP4 expression has also been shown to be significantly elevated in triple-negative BC (TNBC) cells and tissues; and its knockdown markedly inhibits TNBC cell proliferation, invasion and migration, and concurrently downregulates EMT regulatory activities (144). In addition, Moody et al (145) demonstrated that BCL11 transcription factor A (BCL11A), which possesses the ability to promote BC progression, can interact with RBBP4/7; therefore, targeting RBBP4-BCL11A binding may have therapeutic potential.
The role of RBBP7 in BC appears complex and contradictory. Zhang et al (146) observed decreased expression levels of RBBP7 in BC cell lines, and its dysregulation was shown to contribute to BC tumorigenesis. Further research has revealed that RBBP7 is related to estrogen regulation and may affect the early development of BC (64,147). As a component of the Mi2/NuRD complex, RBBP7 regulates TWIST-mediated repression of E-cadherin expression and inhibits BC cell metastasis (148). By contrast, Li and Wang (149) found that recombinant RBBP7 induces EMT and enhances mammary epithelial cell migration. Thus, the mechanism of RBBP7 in BC progression and metastasis requires further investigation.
Notably, in contrast to the observation of Zhang et al (146) of decreased RBBP7 expression in BC, Thakur et al (150) showed that RBBP7 expression was upregulated in 79% of BC cases and its expression was positively correlated with malignancy. RBBP7 may also be involved in the pathogenesis of estrogen receptor-positive pure ductal carcinoma in situ (151). In addition, Mieczkowska et al (152) found that RBBP7 was downregulated in parental G-2 cells from the WAP-T transgenic breast cancer line after surviving traditional cytotoxic combination therapy, suggesting that RBBP7 might be considered a potential therapeutic target for BC in the future.
In summary, both RBBP4 and RBBP7 have demonstrated significant roles in the progression, metastasis and therapeutic potentialities of BC; however, their precise mechanisms and interactions in various BC subtypes warrant deeper exploration.
Cervical cancer
Kong et al (153) observed that RBBP4 overexpression inhibits cervical cancer growth and affects human papillomavirus (HPV)16 transformation by regulating tumor suppressors and oncogenes. Notably, 5-aminole-vulinic acid photodynamic therapy (ALA-PDT), an effective treatment for HPV-related conditions, has been reported to elevate RBBP4 expression in HPV16 immortalized cervical epithelial H8 cells (154). A subsequent decrease in RBBP4 can mitigate the inhibitory effects of ALA-PDT-induced cell proliferation and apoptosis in cervical cancer cells (155). These studies demonstrated that RBBP4 may function as a tumor suppressor in cervical cancer and could serve as a promising therapeutic target for future cervical cancer intervention.
However, studies have also indicated that RBBP4 promotes cervical cancer, influencing EMT and radiotherapy outcomes (156,157). This implicates RBBP4 as a prospective target to boost radiotherapeutic outcomes in patients with cervical cancer. In addition, RBBP7 can be recruited by NK6 homeobox 1, thereby inhibiting the invasive ability of cervical cancer cells (158).
In conclusion, RBBP4/7 have complex roles in cervical cancer and may be potential therapeutic targets. However, the role of RBBP4 in cervical cancer remains controversial, and its mechanism requires further study.
Prostate cancer
Cai et al (159) showed that there is a physical interaction between the tumor suppressor gene EAF2 (encoding ELL associated factor 2) and RBBP4/7, where their overexpression induces cell death in LNCaP prostate cancer cells. High RBBP4/7 expression in prostate adenocarcinoma is also linked to shorter progression-free survival, with RBBP7 interacting with high mobility group box 1 to regulate RNA processing (160). Furthermore, overexpression of RBBP7 suppresses SLUG1/EMT in DU145 cells and exerts tumor suppressive functions in presence of hepatocyte nuclear factor 1β (161). Thus, RBBP4/7 are pivotal in prostate cancer progression and potential therapeutic targets.
Azoospermia or cryptozoospermia
Male infertility, affecting ~7% of men in the general population, is often due to factors such as azoospermia or cryptozoospermia (162). The X chromosome is vital for male reproductive health. Riera-Escamilla et al (163) linked RBBP7 mutations to early spermatogenic failure in an analysis of 2,354 men with azoospermia/cryptozoospermia, revealing that these mutations were more prevalent in this infertile group compared with in control individuals with normozoospermia. RBBP7 forms the CRL4B-RBBP7 complex with CUL4B (encoded by another mutated gene found in infertile men), which contributes to the degradation of HUWE1 and is associated with non-obstructive azoospermia (164). In conclusion, RBBP7 has a central role in male infertility, highlighting the importance of genetic factors in reproductive health.
Urinary system
Bladder cancer
Bladder cancer, affecting >440,000 individuals annually worldwide (165), shows high RBBP7 expression in specimens. Mechanistically, RBBP7 can bind to HDAC1 and specificity protein 1 (SP1), and then bind to the RECK (encoding reversion inducing cysteine rich protein with kazal motifs) promoter at the SP1 site, thereby inhibiting the expression of RECK, which in turn leads to matrix metalloproteinase-9 activation and metastasis, thereby participating in Ras-induced experimental lung metastasis (166). Therefore, RBBP7 could be used as a therapeutic target for Ras-related cancer; however, to the best of our knowledge, there are currently no studies on RBBP4 in bladder cancer.
BK virus-associated kidney disease
Wang et al (167) demonstrated that RBBP7 is highly enriched in BK virus-associated nephropathy (BKVN) tissues and is associated with alterations in various immune cells, such as CD8 naïve cells, induced regulatory T cells, neutrophils and CD8+ T cells. Furthermore, RBBP7 serves as a molecular biomarker for the precise diagnosis of BKVN, effectively distinguishing transplant rejection responses. Thus, targeting RBBP7 as a diagnostic tool may offer novel therapeutic and prognostic opportunities for BKVN in transplant recipients.
Renal cell carcinoma (RCC)
Kim et al (168) showed that RBBP7 is highly expressed in the chromaffin subtype of RCC, but not in traditional RCC. Therefore, RBBP7 could be used as a candidate biomarker in RCC, and its existence and expression patterns might be related to the pathological characteristics of RCC subtypes, providing a novel direction for the diagnosis and treatment of RCC.
Infectious diseases
HIV infection
Wang et al (169) reported increased RBBP4 expression following HIV-1 infection in cell culture models, with RBBP4 knockdown enhancing HIV infection and viral production. RBBP4 suppresses HIV-1 transcriptionally by binding to its long terminal repeats, recruiting nuclear receptor subfamily 2 F group member 1 and HDAC1/2, leading to H3 deacetylation and replication control (170). Similarly, Biswas et al (171) observed elevated RBBP4 levels in HIV-2-infected monocyte-derived macrophages, and Xu et al (172) reported that thieno[3,4-d] pyrimidine treatment in infected cells increases RBBP4 levels and activates the NF-κB pathway, suppressing HIV-1. Collectively, these findings demonstrate a critical role for RBBP4 in the regulation of HIV infection and suggest its potential as a therapeutic target for HIV management.
HPV infection
Oral squamous cell carcinoma (OSCC) and oropharyngeal squamous cell carcinoma (OPSCC) constitute a major global public health burden, and there is an association between infection with high-risk types of HPV and OSCC risk (173). Lohavanichbutr et al (174) identified differential expression of RBBP4 in HPV-positive vs. HPV-negative oropharyngeal cancer. Wurlitzer et al (175) performed a mass spectrometric comparison of eight HPV-positive and nine HPV-negative OPSCC cases, and found that RBBP4/7 was expressed at higher levels in HPV-positive OPSCC.
In cervical cancer, a major HPV-related cancer, RBBP4 mediates the transforming activity of HPV16 (153) and is upregulated by ALA-PDT in HPV16 immortalized cervical cells (154). These findings indicated that RBBP4 plays a key role in HPV infection; however, the specific mechanism still needs further exploration. Moreover, current research on the role of RBBP7 in HPV infection is insufficient.
Plasmodium infection
Kaushik et al (176) discovered that the homologs of RBBP4/7 in Plasmodium falciparum (PfRBBP4/7, PF3D7_0110700) retain the β-helical conformation and binding interfaces, exhibit significant interspecies differences, and show stage-specific expression in the asexual blood stages of the parasite, increasing from the ring stage to the schizont stage, and localizing in the nucleus. Furthermore, PfRBBP4/7 have been shown to interact with histone H4, suggesting their role in chromatin assembly and remodeling pathways in P. falciparum. As CAF-1 family members, they show structural and functional consistency. PfRBBP4, central in malaria biology with 108 PPIs, emerges as a potential antimalarial drug target (177). Thus, the function of PfRBBP4/7 in P. falciparum illustrates their potential as targets to develop novel antimalarial interventions.
5. RBBP4/7 as potential targets for human disease treatment
In the realm of targeted therapy research focused on RBBP4/7, these proteins have demonstrated significant potential in the treatment of various diseases, particularly in modulating therapeutic outcomes. For example, increased expression of RBBP4 has been linked to mitigating lead-induced neuronal apoptosis, suggesting a potential role in alleviating lead poisoning and related neurological disorders (178). Additionally, the interaction of RBBP4 with the efficacy of multiple drugs has been extensively studied, including its role in enhancing the sensitivity of GBM cells to TMZ (56,95), suppression of LC cell malignancy via ropivacaine by downregulating RBBP4 (179), and the identification of the circ-0110498/miR-1287-5p/RBBP4 axis as a novel target for overcoming cisplatin resistance in NSCLC (85). RBBP4 is also considered a potential target for treating CRC with PPD (119). In therapeutic contexts, RBBP4 expression is significantly increased in cervical cancer cell lines treated with ALA-PDT (155), and upregulation of RBBP4 has been found to induce radiosensitivity in BC, melanoma and TNBC (180). Conversely, reduced levels of RBBP7 may be associated with survival rates and chemoresistance phenotypes in basal-like BC (152).
PPIs play a pivotal role in cellular functions, and modulating PPIs offers a novel therapeutic avenue. It has been reported that blocking the interaction between BCL11A and RBBP4 reduces the cancer stem cell population in TNBC (145). Furthermore, compounds, such as bittersweet alkaloid II, may aid in AD treatment by stabilizing the RBBP4-FOG1 complex (103). Additionally, peptides designed by Hart et al targeting the RBBP4/MTA1 interaction interface show potential as future therapeutic strategies for disrupting epigenetic regulation mechanisms in various types of cancer (181). Despite the potential of small molecules or peptides targeting RBBP4/7, challenges such as low oral bioavailability and poor in vivo stability remain, necessitating further research to overcome these obstacles.
Emerging research has consistently linked elevated RBBP4/7 expression to poorer prognosis across various cancer types (Table V), underscoring their pivotal role in disease therapy. Despite the evident potential of RBBP4/7 in treating various diseases, the success of targeted strategies remains elusive, possibly due to the complex biological roles of RBBP4/7 and their involvement in multiple protein complexes. Future research should investigate the mechanisms of RBBP4/7 to develop targeted and effective treatment approaches. This includes a deeper understanding of the specific roles of RBBP4/7 in different cell types and disease states, identifying the molecular networks interacting with RBBP4/7, studying their expression and functional variations across diseases, and validating therapeutic interventions targeting RBBP4/7 in preclinical and clinical studies. Through these efforts, the scientific groundwork may be laid for novel treatment methods based on RBBP4/7, offering more personalized and effective therapeutic options for patients.
6. Conclusion and future perspectives
RBBP4/7 are conserved proteins ubiquitously present in various organisms, which function in chromatin modification and gene regulation across species. However, their specific structure, expression patterns and molecular mechanisms may differ depending on the organism. For example, in P. falciparum, Drosophila, zebrafish and Saccharomyces cerevisiae, the structure of RBBP4 might resemble that in humans; however, there could be unique structural domains or adjustments (18,80,96,176). Moreover, in these organisms, RBBP4/7 primarily function during developmental and reproductive stages. By contrast, in humans, RBBP4/7 are expressed across diverse cells and tissues, and are associated with cell cycle regulation and gene transcription.
As histone chaperones, RBBP4/7 regulate various cellular processes and are implicated in a variety of human diseases, thus the future of RBBP4/7 research is promising. However, the expression patterns of RBBP4/7 exhibit significant variability in certain tumor types. This variability is attributed to the diverse roles of RBBP4/7 within multiple functional complexes, whose impact on tumorigenesis is intricately linked to the specific actions of these complexes, which vary with the cellular context and tumor type. In addition, research into gene mutations and DNA methylation abnormalities of RBBP4/7 in diseases remains limited, with mutations in RBBP7 identified only in cases of early spermatogenic failure (163). This underscores an important area for further investigation. Further studies of the complex molecular functions of RBBP4/7 may improve the understanding of cellular processes and disease pathways, leading to the development of innovative therapies for a variety of human diseases and cancers. Furthermore, exploring RBBP4/7 as potential biomarkers could improve diagnostic accuracy, enabling early detection and personalized medicine approaches.