Controversial roles of hepatocyte nuclear receptor 4 α on tumorigenesis (Review)
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- Published online on: March 4, 2021 https://doi.org/10.3892/ol.2021.12617
- Article Number: 356
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Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Hepatocyte nuclear receptor factor 4 α (HNF4α; NR2A1) is a highly conserved orphan member of the nuclear receptor superfamily. It was first cloned by Frances Sladek in James Darnell's laboratory for nuclear factor expression in the liver and was demonstrated to act as a central regulator of gene expression in certain types of cells that play critical roles in metabolic homeostasis, including hepatocytes, enterocytes and pancreatic β cells (1). In humans, HNF4α gene is widely expressed in the liver, kidney, pancreas, stomach, small intestine and colon (2), is located on chromosome 20 and comprises at least 12 exons. Two promoters of HNF4α, named P1 and P2, have been identified to drive the expression of at least six different splicing variants, HNF4α1-α3 and HNF4α7-α9 (2–4). Four variants have been well characterized: HNF4α1 and HNF4α2 from the P1 promoter and HNF4α7 and HNF4α8 from the P2 promoter. HNF4α3 (P1-driven) and HNF4α9 (P2-driven), which both have a different F domain, are less well characterized, although some recent studies reported that these isomers are expressed in human pancreas and may play a role in the development of diabetes (4).
HNF4α is classified as an orphan nuclear receptor for which ligand has not been found yet, and its regulatory role remains unclear (5). Previously, research on HNF4α ligands have reported conflicting evidence. For example, long-chain fatty acids have been shown to bind as acyl-CoA thioesters to the ligand binding pocket of HNF4α and to act as transactivators or antagonists, depending on their chain length and saturation (6–9). However, these fatty acids are bound firmly and not exchangeable, and seem to bind irreversibly to the receptor, suggesting that they might act more as structural co-factors than classical regulatory ligands (10,11). Conversely, HNF4α expressed in mammals was shown to be bound to the essential fatty acid linoleic acid (LA; C18:2), which is considered as a potential endogenous ligand of HNF4α (12). Although this binding is reversible, it does not appear to have any significant effects on the transactivation function of HNF4α (5,12). Recently, several synthetic HNF4α antagonists were reported to bind to the ligand binding domain (LBD) of HNF4α with high affinity and to regulate the expression of known HNF4α target genes. In particular, these antagonists were found to be selectively cytotoxic to cancer cells in vitro and in vivo (1,13). For example, one small molecule, 1-(2′-chloro-5′-nitrobenzenesulfonyl)-2-methylbenzimidazole (BIM5078), which has been discovered by a novel high-throughput screening for insulin promoter modulators (14) exhibited a dose-response inhibition of the expression of known HNF4α target genes (1). BIM5078 was demonstrated to be structurally similar to FK614, which is a PPARγ agonist formerly described as a therapeutic agent for type II diabetes (15). BIM5078 may directly bind and interact with the LBD of HNF4α repress target genes and may be cytotoxic to hepatocellular carcinoma cells (1).
HNF4α is a highly conserved member of the nuclear receptor superfamily of ligand-dependent transcription factors, acts as a homodimer and plays a critical role in early liver morphogenesis, fatal liver development, liver differentiation and metabolism by regulating the transcription of genes involved in each of these biological processes (5,16–18). Numerous studies have also reported the central role of HNF4α in regulating a number of genes, such as cytochrome P450 genes (CYP2C8, CYP2C9, CYP2C19, CYP7A1, CYP3A4 and CYP8B1) that essential for the xenobiotic and drug metabolism, to protect individuals from toxic effects and provide key building blocks and nutrients to promote the growth or maintain the survival of the organism (5,19–21). Due to its multiple functions, HNF4α is described as a master regulator in multiple signal channels. For example, HNF4α-deficient embryonic livers showed decreased expression of most hepatic factors, including apolipoprotein B, liver fatty acid-binding protein and microsomal triglyceride transfer protein as well as retinol-binding protein, which indicated that HNF4α is a hepatocyte differentiation factor critical for maintaining normal liver structure and normal liver development (12,22–25).
Similarly, HNF4α was demonstrated to promote the differentiation of intestinal epithelial cells (26) and embryonic development of the colon in mice (27). HNF4α also serves an important role in hepatic progenitor cells differentiation by governing the expression of the transcription factors, including forkhead box protein A2, (T-Box transcription factor 3), hematopoietically-expressed homeobox protein, GATA4 and GATA6 that control the hepatocyte cell development and regeneration (28). Other studies reported that ectopic expression of HNF4α significantly inhibits the proliferation of HEK293 (29) and pancreatic INS-1β-cells (30). Furthermore, HNF4α may act as a mesenchymal-to-epithelial transition (MET)-inducing factor in hepatocytes (31–33), and accumulated evidence indicates that HNF4α is involved in inflammatory networks (34,35).
The present review will summarize the expression patterns, alterations and regulatory effects of HNF4α in human cancers, and introduce the novel functions of this ancient receptor.
Expression pattern of HNF4α in human cancers
Using the Broad Institute Fire Browse portal (http://firebrowse.org/), we investigated the expression patterns of HNF4α gene in 38 human cancers compared with normal controls. The results demonstrated that the levels of HNF4α transcription varied among different types of cancer (Fig. 1). Compared with the matched normal tissues, HNF4α expression was upregulated in 11 types of tumors tissue and downregulated in 14 types of tumors tissue. The expression of HNF4α was the highest in liver hepatocellular carcinoma and the lowest in pheochromocytoma and paraganglioma. In both types of cancer, HNF4α was decreased in cancer tissues compared with normal tissues. These findings indicated that the expression of HNF4α may be regulated in tissue-specific and cancer type-dependent manners. Because there are two promoters (P1 and P2) of HNF4α gene, the differential expression pattern and dysregulation of HNF4α in cancer cells could be partially due the alternative promoter use and splicing (36–38). The distribution of differential promoter-driven HNF4α isoforms have been well defined using immunohistochemical analysis, which was associated with the pathogenesis of certain types of cancer (36). For example, downregulation of P1-driven HNF4α isoforms expression is involved in tumor metastasis and poor prognosis of colorectal cancer (CRC) (37). Some studies on gastric cancer suggested that P1-driven HNF4α isoforms negative expression may be considered as a useful marker for mucin phenotypic classification (38). In addition, HNF4α appears to encode multiple isoforms from both promoters by selective splicing, with different transcriptional functions (39–41). However, the precise regulation mechanism of differential promotor-driven HNF4α isoforms in human carcinogenesis is not fully understood.
Alterations of HNF4α in human cancers
The frequency of HNF4α gene alterations, including mutation, deletion, fusion and amplification, was determined across multiple types of cancer using the cBioPortal for Cancer Genomics database (http://www.cbioportal.org), which contains 147 common cancer studies that included the clinicopathological characteristics of almost 23,000 patients. All searches were carried out according to the online instructions of cBioPortal website. By pan-cancers analysis, we found that amplifications and mutations were the most common alterations of HNF4α in human cancers, particularly in colorectal and uterine cancers (Fig. 2). Notably, HNF4α alterations were mostly observed in one of the CRC studies (TCGA, Pan-Can) (42), in which HNF4α was altered in 59 cases of 594 patients (9.93%), where 48 cases (81.4%) of these alterations were amplifications. As a core transcription factor, HNF4α was demonstrated to be associated with the tumorigenesis and development of CRC (43). However, the expression and functional role of HNF4α in CRC was controversial (44). It was reported that HNF4α expression is downregulated in CRC specimens and is positively correlated with pT typing, lymph node metastasis, distant metastasis and clinical stage in patients with CRC (45). Furthermore, HNF4α plays an inhibitory role in the progression of colon cancer by interacting with Wnt/β-catenin/transcription factor 4 (TCF4) pathway and influencing apoptosis and cell cycle progression (45). In addition, P2-driven HNF4α has been shown to promote inflammation and carcinogenesis in colon (40,44). Numerous proteins, including RAD50, PARP1 (double strand break repair protein, poly(ADP-ribose) polymerase 1) and DNA-PKCS (DNA-dependent protein kinase) have been demonstrated to interact with HNF4α in order to improve the response of CRC cells to DNA damage (46). These different functional roles and controversial reports may be due at least in part to the different transcriptional or translational changes in HNF4α gene.
The protein expression level, sub-nuclear distribution and post-translational modifications (PTMs) of HNF4α are also critical determinants of its transactivation potency. Yokoyama et al (47) analysed the PTMs in HNF4α proteins by mass-spectrometry (MS) and identified eight PTMs, including phosphorylation sites (S142, T166, S167 and S436), ubiquitylation sites (K234 and K307) and an ubiquitination and acetylation site at K458. Zhou et al (48) reported that the stability of HNF4α was regulated by SUMOylation in a human embryonic stem cell-based model, and that it serves a critical role during hepatocellular differentiation. Daigo et al (49) validated and identified several phosphorylation sites (Ser134, Ser133, Ser158 and Thr420 + Ser427) of HNF4α by MS/MS neutral loss ion spectra analysis, suggesting a contribution of phosphorylation status alterations to the multi-functional roles of HNF4α. Due to the development and application of high-throughput genomic and proteomic technologies, the expression and modification of HNF4α have become the focus of attention in the recent decades. However, the post-transcriptional role of HNF4α in the carcinogenesis process remains unclear.
Regulatory roles of HNF4α in human cancers
Increasing evidence indicated that disruption of HNF4α expression is widely involved in the initiation and development of numerous types of human cancer, including gastric, hepatocellular and colorectal carcinomas (36). Many studies have focused on clarifying the regulatory role and underlying mechanism of HNF4α in cancer. However, there have been conflicting reports about the role of HNF4α in promoting and inhibiting cancer in humans.
Tumor suppressive role of HNF4α
HNF4α is the main regulator of liver specific gene expression and has strong tumor suppressive activity. The tumor suppressive effect of HNF4α was determined after discovering that HNF4α expression was lost or significantly decreased in several human cancers, and that restoration of HNF4α expression could inhibit cancer cell proliferation in different types of cancer, including mouse liver cells (50–53), intestinal cancer (54), lung endothelial cells and embryonic cancer (55), islet tumor cells (30) and embryonic kidney cells (29). However, the underlying mechanism of HNF4α-mediated tumor inhibition is not fully understood. The mechanisms by which HNF4α can inhibit cancer in humans are therefore summarized in the present review (Fig. 3 and Table I).
A recent study from our group demonstrated that HNF4α expression is decreased in prostate cancer cells, and that ectopic overexpression of HNF4α could significantly inhibit prostate cancer cell proliferation, induce cell-cycle arrest at G2/M phase and trigger the cellular senescence via activation of p21 signal pathway in a p53-independent manner and direct transactivation of cyclin-dependent kinase inhibitor 1, suggesting that HNF4α might have a tumor suppressor role in prostate cancer cells (56). Hwang and Sladek (57) reported that HNF4α competes with the oncoprotein c-Myc for targeting the p21 promoter in order to activate its expression, which could significantly inhibit HCC and colorectal carcinoma cell proliferation. These findings confirmed the critical role of p21 protein in HNF4α-mediated tumor growth inhibition. The loss of HNF4α expression may therefore be considered as a key event in the development and progression of cancer; however, its underlying mechanism remains to be further investigated. Previous studies on the HNF4α gene knockout mouse model reported the negative correlation between deletion/deletion expression of HNF4α and activation of c-MYC network, which involves many pro-growth genes, such as bone morphogenetic protein 7 (58), FUS RNA binding protein, SET nuclear proto-oncogene, ribonucleotide reductase regulatory subunit M2 and Myc (59,60). Cyclin D1 was also demonstrated to directly bind to HNF4α and cause a decrease in downstream genes expression (61). Previous studies in renal cell carcinoma reported that decreased HNF4α expression is positively correlated with e-cadherin expression, suggesting a poor prognosis in patients (62–64). Furthermore, HNF4α expression is blocked by mutated IDH, which could promote biliary cancer progression (65). Previous studies in hepatocellular carcinoma (HCC) demonstrated that HNF4α exhibits a decreased expression pattern, which could inhibit hepatocellular carcinoma growth by downregulating miR-122 expression and inhibition of the ADAM metallopeptidase domain 17 and NOTCH signal pathway (52,66,67).
Previous studies demonstrated that non-coding RNAs (ncRNAs), including micro (mi)RNAs, long ncRNAs and circular (circ)RNA, serve important roles in the regulation of HNF4α-mediated transcriptional level (68–70) (Fig. 3B). Takagi et al (71) reported that HNF4α expression is decreased in HepG2 cells and is negatively regulated by miR-24-mediated mRNA degradation and miR-34a-mediated transcriptional suppression, affecting therefore the expression of metabolic enzymes and cellular biology (68,72). miR-34a, miR-34c-5p and miR-449a are reported to share the same target elements located at two distinct locations within the 3′-UTR of HNF4α, which overexpression could significantly repress HNF4α protein level by blocking mRNA translation (68,73). Koh et al (74) demonstrated that high expression level of miRNAs from let-7 family could regulate self-renewal and differentiation pathways by suppressing the downstream target HNF4α. It was reported that HNF4α expression is decreased in HCC via nuclear factor kappa B (NF-κB) mediated miR-21 upregulation (70). In addition, decreased expression of HNF4α could promote HCC metastasis by regulating the expression and translocation of RelA and affecting NF-κB activation (70). Zhan et al (75) demonstrated that HNF4α could bind to the promotor region of circRNA_104075 to stimulate its expression, and that circRNA_104075 can act as a ceRNA able to upregulate YAP-Hippo pathway by absorbing miR-582-3p. ncRNAs are the most abundant regulatory factors that possess great post-transcriptional regulatory potential. However, the underlying mechanism by which miRNAs act and regulate HNF4α expression remains to be further investigated.
HNF4α has been reported to suppress hepatocyte epithelial-mesenchymal transition (EMT) and cancer stem cell generation via inhibition of β-catenin signalling pathway (45,53). EMT is a critical developmental process during cancer invasion and metastasis. Wnt-β-catenin signalling pathway plays a crucial role in triggering EMT progression in both embryonic development and tumorigenesis (33,76,77). Previously, HNF4α was reported to be a potential EMT regulator in HCC cells (77), since its ectopic expression induces MET and blocks HCC progression (25). Previous studies demonstrated that the repression of mesenchymal program of HNF4α is subsequent to inhibition of Snail (31) and competition with β-catenin for binding to TCF4 in HCC cells (77,78). Other studies also indicated that HNF4α expression is lost or significantly decreased in cirrhotic tissues and decreased in HCC tissues compared with healthy tissues (50,53,79). Restoration of HNF4α expression by an adenovirus-mediated gene delivery system could attenuate hepatocyte EMT during hepatocarcinogenesis through inhibition of Wnt/β-catenin signalling pathway (77,80,81), significantly reducing the proportion of cells with stem cell gene expression and CD133+ and CD90+ cells, which are considered as tumor stem cells in the start and development of HCC (82). These findings highlighted the central role of HNF4α in the Wnt-β-catenin/snail signalling pathway involved in the EMT/MET progression, which could be a critical inhibitory mechanism for tumorigenesis.
Oncogenic roles of HNF4α
Considering the differences in the biologic properties of experimental systems and tumor samples, increased conflicting reports about the role of HNF4α in HCC progression and in several other types of cancer (51,83–87; Table II) have been observed. The known oncogenic roles of HNF4α in human cancers are summarized in Fig. 4.
Darsigny et al (88) demonstrated that HNF4α is significantly upregulated in CRC tissues compared with adjacent normal epithelial tissues and serves a critical role in promoting gut tumorigenesis by directly targeting the promoter of cytochrome P450 family 2 subfamily B member 6 protein and glutathione S-transferase kappa 1 gene against spontaneous and 5-fluorouracil chemotherapy-induced production of ROS in CRC cell lines, indicating the oncogenic role of HNF4α in human carcinogenesis (89). Another study on human primary mucinous tumors demonstrated that increased HNF4α expression is associated with higher tumor grade, suggesting a carcinogenic role of HNF4α in mucinous tumors (90). Similarly, a study on neuroblastoma (NB) reported that HNF4α expression is significantly upregulated in clinical neuroblastoma tissues as an independent prognostic factor for poor patient outcomes (91). HNF4α knockdown can suppress the invasion, metastasis and angiogenesis of NB cells in vitro and in vivo through downregulating matrix metalloproteinase 14 (MMP-14) by direct binding to the promoter region of MMP-14, an inhibitory effect that can be neutralized by ectopic expression of HNF4α (91). HNF4α was also found to be upregulated in all invasive mucinous adenocarcinoma (IMC) of the lung determined according to tissue array, indicating that HNF4α could be considered as a useful marker for IMC of the lung (92). HNF4α expression was also found to be increased in paediatric NB tissues and negatively regulated by miR-34a to promote cancer cell proliferation and invasion (93). A study in pancreatic cancer (PDAC) indicated that HNF4α is increased in cancer tissues compared with adjacent tissues (94). HNF4α is required for pancreatic cancer cell proliferation and promotes resistance to gemcitabine by downregulating hENT1 (94).
Recent studies have reported that HNF4α is significantly upregulated in gastric cancer (GC), head and neck squamous cell carcinoma and pancreatic adenocarcinoma tissues compared with normal tissues (94,95). In particular, HNF4α acts by sustaining an oncogenic metabolism in GC via the direct binding to the promoter region of isocitrate dehydrogenase-1 (IDH-1), which is a key enzyme for TCA cycle required for GC development (95). However, mutated IDH-1 and IDH-2 can inhibit HNF4α to block hepatocyte differentiation and promote the development of premalignant biliary lesions and progression to metastatic HCC (65). Chang et al (96) reported that HNF4α is upregulated by AMPK signalling and acts as an upstream regulator of the WNT signal pathway through its target gene Wnt family member 5A in GC. In addition, the overexpression of HNF4α in GC tissues is significantly associated with tumor stage and lymph node metastasis in patients with GC, which may cause drug resistance to multiple chemotherapeutics due to regulation of cell apoptosis and Bcl-2 expression (97). Nakajima et al (98) demonstrated that HNF4α is a direct target gene of kruppel like factor 5/GATA binding protein (GATA)4/GATA6 that can interact with GATA6 and contribute to the development of mucinous-type lung adenocarcinomas and GC (99). A previous study from our laboratory demonstrated that HNF4α can be significantly upregulated in prostate cancer cells-derived prostatospheroids, suggesting that HNF4α may also work in the regulation of prostate cancer stem cells (100). In summary, HNF4α had demonstrated an upregulation pattern and an oncogenic role in many types of cancer, suggesting that HNF4α may be considered as a therapeutic target in numerous human carcinomas.
Conclusions
As an important regulator of tumorigenesis and tumor development, HNF4α is expressed at different levels in different types of tumor and serves various roles that are tissue-specific. This suggests the ubiquitinal expression patterns of HNF4α and the changes in HNF4α expression, as well as the controversial mechanisms that may be involved in cancer progression, which provide further clues to the better understanding of HNF4α role in cancer. Over the years, numerous studies have provided significant advances in the role of HNF4α in human cancers; however, the underlying mechanisms involved remain unclear and require urgent further investigation. Considering the different roles of HNF4α isoforms in the transcriptional control of cell proliferation, EMT, stemness and other cellular processes in different types of cancer, further research should focus on the potential therapeutic approaches of targeting HNF4α.
Acknowledgements
Not applicable.
Funding
This work was partially supported by the Shenzhen Science and Technology Program (Basic Research Project; grant no. JCYJ20180228163919346), the National Natural Science Foundation of China (grant no. 81802566) and Longhua Science and Technology Innovation Fund (grant nos. 2020013 and 2020003).
Availability of data and materials
The data that support the findings of this study are available from The Cancer Genome Atlas (http://cancergenome.nih.gov/).
Authors' contributions
ZW and YZ drafted the manuscript. ZW obtained funding, drafted and revised the manuscript. QD, JZ and HL helped to revise the manuscript for important intellectual content. ZW and HL confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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