In various solid tumors, high expression of CHD4 is often associated with increased tumor aggressiveness, enhanced metastatic potential, and poor prognosis, suggesting that its role in tumor progression is crucial (17). Recent studies have shown that CHD4 does not function through a single molecular pathway but is more likely to influence tumor cell behavior by regulating multiple interconnected transcriptional processes (18–20).

Of these transcriptional regulatory networks (TRNs), oncogenic signaling pathways form an important basis for CHD4′s involvement in tumor migration and invasion. Wingless/Integrated (Wnt)/β-catenin is a typical signaling pathway through which CHD4 regulates tumor metastasis. In gastric cancer (GC), CHD4 interacts with myosin heavy chain 9, thereby inhibiting the activity of glycogen synthase kinase-3β and stabilizing β-catenin, which activates the Wnt/epithelial-mesenchymal transition (EMT) signaling pathway, thereby promoting tumor invasion and metastasis (18). Similar regulatory patterns can also be observed in ovarian cancer, where CHD4 enhances nuclear accumulation and transcriptional activity of β-catenin through the enhancer of zeste homolog 2 (EZH2)/β-catenin signaling axis (19). These studies suggest that CHD4 may repeatedly participate in the regulation of β-catenin-related transcriptional processes in different tumor types, thereby promoting EMT and tumor metastasis. In addition to the Wnt/β-catenin pathway, CHD4′s influence on tumor cell migration is also closely related to cytoskeleton-related signaling pathways. In non-small cell lung cancer, CHD4 activates the Ras homolog gene family, member A (RhoA)/ρ-associated protein kinase signaling pathway by regulating PHD finger protein 5A, thereby enhancing the proliferation and migratory ability of tumor cells (20). This mechanism suggests that CHD4 might help regulate tumor cell movement by affecting cytoskeletal dynamics and act as a bridge between different signaling networks.

The regulatory role of CHD4 is not limited to cell migration but also extends to regulation of tumor cell proliferation. For example, in breast cancer (BC), CHD4 upregulates the transcriptional levels of estrogen receptor-α (ERα) and inhibits its ubiquitination degradation, thereby continuously enhancing the transcriptional activity of the ERα signaling pathway (21). This phenomenon indicates that CHD4 can not only regulate classical signaling pathways but might also further amplify oncogenic signals by stabilizing key transcription factors (TFs).

A hypoxic state in the tumor microenvironment (TME) further expands the functions of CHD4, which can co-activate hypoxia-inducible factors 1α and 2α (HIF-1α, HIF-2α), synergistically promoting the transcription of hypoxia-responsive genes with the HIF complex. Under normoxic conditions, CHD4 is already enriched in the promoter regions of HIF target genes and promotes the loading of RNA polymerase II via p300, while HIF activation under hypoxic conditions further enhances the recruitment of CHD4 to chromatin, forming a positive-feedback regulatory loop and amplifying the hypoxia response signal (22). This process suggests that the chromatin-binding and transcriptional regulatory activity of CHD4 may be further enhanced under hypoxic conditions. Such changes may further affect the downstream TRN of CHD4. For example, CHD4 can promote citrullination of the key glycolytic enzyme pyruvate kinase muscle isozyme 2 (PKM2) by regulating the expression of peptidyl arginine deiminases 1 and 3 (PADI1, PADI3), thereby altering PKM2′s metabolic regulatory mode and enhancing glycolytic activity (23). Given that enhanced glycolysis is an important means by which tumor cells adapt to hypoxic environments, this CHD4-PADI1/3-PKM2 regulatory axis may be a mechanism by which CHD4 participates in tumor metabolic adaptation under hypoxic conditions.

In addition to signaling and metabolic regulation, CHD4 also participates in tumorigenesis by maintaining the silencing of tumor suppressor genes. In colorectal cancer (CRC), CHD4 is recruited to DNA damage sites and further recruits DNA methyltransferases (DNMTs) to establish abnormal DNA methylation and maintain suppressive chromatin structures at the promoter regions of multiple tumor suppressor genes (24). Moreover, CHD4 can synergize with DNMT1 and DNMT3B to jointly maintain the stable silencing of tumor suppressor genes through multiple epigenetic mechanisms, including DNA methylation, histone deacetylation, and nucleosome remodeling (25).

It is worth noting that in certain tumor types, CHD4 also helps maintain chromatin structural homeostasis. For example, in Ewing sarcoma, CHD4 deletion leads to chromatin structural disorders and induces spontaneous DNA damage accumulation, thereby significantly inhibiting tumor cell proliferation (13). This phenomenon suggests that the role of CHD4 may be highly dependent on the context of the specific tumor environment.

Taken together, these studies paint an increasingly clearer picture: CHD4 reshapes tumor cell behavior through multiple mechanisms, including regulation of signaling pathways, microenvironment adaptation, metabolic reprogramming, and epigenetic regulation, thereby promoting tumor progression.

Although numerous studies have shown that CHD4 has oncogenic effects in various tumors, under specific transcriptional regulatory conditions, it may also exhibit tumor-suppressive functions. For example, in luminal-type BC, the TF transcriptional repressor GATA binding 1 (TRPS1) can recruit the CHD4/NuRD (MTA2) complex to the promoter region of tp63, inhibiting tp63 expression via chromatin remodeling and thereby limiting tumor cell migration and invasion (26). Further research has found that TRPS1 can also recruit CHD4 to the regulatory region of sex-determining region Y (SRY)-related high-mobility group (HMG) box 2 (SOX2), inhibiting SOX2 transcription by altering local chromatin structure (27). Since SOX2 is an important factor for maintaining cancer stem cell characteristics, the TRPS1-CHD4-SOX2 regulatory axis can exert tumor-suppressive effects by limiting tumor stemness. In addition, CHD4 can help inhibit tumor progression by regulating enhancer activity. Studies have shown that AT-rich interactive domain-containing protein 1A (ARID1A) promotes the binding of the CHD4-zinc finger myeloid, Nervy, and deformed epidermal autoregulatory factor 1 homolog, or MYND, type containing 8 (ZMYND8) complex to super-enhancers by maintaining the distribution of the histone variant H3.3 on chromatin, thereby exerting transcriptional inhibitory effects on genes related to EMT and cell migration. When ARID1A function is lost, the transcriptional inhibition mediated by CHD4-ZMYND8 is disrupted, leading to excessive activation of super-enhancers and promoting tumor cell migration and invasion (16).

The results of the aforementioned studies indicate that when CHD4 synergizes with specific TFs or chromatin regulators, it can limit the activation of abnormal transcriptional processes by maintaining suppressive chromatin structures, thereby exerting tumor-suppressive effects under specific contexts.

In addition to changes in expression levels, mutations to the Chd4 gene can also reshape the TRN related to tumor progression. It has been shown that Chd4 mutations do not necessarily lead to complete loss of its function but may reshape the cell's transcriptional process by altering its chromatin-remodeling activity or target gene selectivity. This view was first supported by functional studies. Researchers used the Drosophila homolog dMi-2 as a model to systematically analyze various missense mutations of Chd4 obtained from patients with tumors. The results revealed that these mutations could alter the ATPase activity, nucleosome-binding ability, and nucleosome-sliding efficiency of Chd4 in a mutation-specific manner. Some mutations reduce ATP hydrolysis ability or weaken chromatin-remodeling efficiency, while others may enhance related activities (28). Similar mutation effects have also been observed in human tumors. For example, in endometrial cancer, the common mutations R975H and R1162W can reduce CHD4 protein stability and weaken its function, thereby activating the transforming growth factor-β signaling pathway and enhancing cancer cell stemness characteristics (29). Another study also found that the R975H mutation could activate multiple oncogenic signaling pathways, such as tumor necrosis factor-α/nuclear factor κ-light-chain-enhancer of activated B cells, Kirsten Ras oncogene homolog, mammalian target of rapamycin, and myelocytomatosis oncogene; and promote polarization of tumor-associated macrophages toward an immunosuppressive M2 phenotype, thereby enhancing tumor immune escape ability (15). In addition to missense mutations, some truncating mutations located in the SNF2 domain (such as p.Trp736Ter) may also disrupt the integrity of the NuRD complex and lead to abnormal chromatin remodeling, thereby promoting tumorigenesis and metastasis (30). In conclusion, the effects of Chd4 mutations on tumor progression show significant heterogeneity.

DDR, the core defense system allowing cells to maintain genomic integrity, encompasses multiple stages such as damage recognition, signal transduction, chromatin remodeling and DNA repair (31). It has been shown that dynamic changes in chromatin structure are an indispensable regulatory link in the DDR chain. As an important chromatin-remodeling factor, CHD4 plays a crucial role in this process (32).

After the occurrence of DNA double-strand breaks (DSBs), cells first rapidly recognize the damaged sites through poly [adenosine diphosphate (ADP)-ribose] polymerase 1/2 (PARP1/2)-mediated poly-ADP-ribosylation reactions. Poly [adenosine diphosphate (ADP)-ribose] (PAR) chains not only serve as a scaffold for recruiting DNA repair factors but they can also induce local chromatin relaxation, thereby promoting recruitment of repair factors (33). Studies have demonstrated that at this stage, CHD4 can be rapidly recruited to DNA damage sites in a PAR-dependent manner and participate in early chromatin remodeling (32). In the early stages of DDR, CHD4 usually works in concert with the acetyltransferase p300. P300 reduces chromatin compaction through histone acetylation, while CHD4 relies on its ATPase activity to regulate nucleosome positions. This maintains a relatively open and dynamic chromatin state in the damaged region, thereby providing optimal conditions for the entry of DNA repair factors (34).

As DDR signals are further amplified, ataxia telangiectasia mutated protein (ATM) kinase is activated and initiates a series of signal cascades. Really Interesting New Gene finger protein 8 (RNF8)-mediated histone ubiquitination is considered an important step in signal amplification. RNF8 can catalyze the ubiquitination modification of H2A and H2A histone family member X, providing a molecular platform for the stable binding of DNA repair complexes such as breast cancer type 1 (BRCA1) (35). During this catalytic process, CHD4 enhances the spatial accessibility between RNF8 and its substrates by regulating the chromatin structure around the damaged sites, thereby promoting formation of ubiquitin chains. Meanwhile, RNF8 can also promote recruitment of additional CHD4 to the damaged region via a non-catalytic mechanism, forming a positive-feedback regulatory loop at damaged sites and further stabilizing the assembly of DNA repair complexes (36).

Regulation of DDR also relies on the synergistic action of multiple chromatin regulatory factors. For example, the silent mating type information regulation 2 homolog 6 (SIRT6)/CHD4 pathway is considered an important regulatory branch for DSB repair. SIRT6 can act as a damage sensor and promote early signal amplification by activating PARP1 (37); under ATM-dependent conditions, interaction between SIRT6 and CHD4 is significantly enhanced, and they jointly promote chromatin remodeling at the damaged sites and homologous recombination repair (HRR). When ATM activity is inhibited or absent, this synergistic effect is significantly weakened, leading to a decrease in HRR efficiency (38). In addition, it has been demonstrated that CHD4-mediated chromatin remodeling may also affect the choice of DNA repair pathways via regulation of R-loop-related mechanisms. When DSBs occur in transcriptionally active chromatin regions, the bromodomain and extra-terminal domain family protein bromodomain-containing protein 3 can recruit CHD4 and work in concert with the Tat interacting protein, 60 kDa complex to initiate chromatin remodeling, promoting histone H4-lysine 16 acetylation and expelling heterochromatin protein 1. This inhibits the binding of p53 binding protein 1 at damaged sites and promotes the recruitment of BRCA1 and R-loop-related repair factors (39), a process that ultimately promotes R-loop-mediated HRR. Taken together, these findings suggest that CHD4 can affect DNA repair pathway selection by regulating R-loop-related chromatin remodeling, thereby maintaining genomic stability.

As DNA damage is gradually repaired, cells must terminate DDR signals in a timely manner and restore normal cell cycle progression. The ATM-checkpoint kinase 2-p53 signaling axis plays a central role in this process: p53 can induce p21 expression to mediate G1/S checkpoint arrest, thereby providing a window of time for DNA repair (40). It has been revealed that as a core subunit of the NuRD complex, CHD4 can mediate p53 deacetylation and inhibit its transcriptional activity (41). This suggests that CHD4 may be involved in terminating DDR signals and restoring cell cycle after DNA repair is completed.

In the more complex chromatin regulatory network (CRN), the overall synergistic action of the NuRD complex is also crucial for DDR. For example, the R-loop structure formed on DNA damage can promote the establishment of chromatin boundaries via the GATA zinc finger domain containing 2B/NuRD complex in the damaged region, thereby limiting excessive DNA end resection and maintaining the stability of the repair process (42). In addition, in the PARP-dependent repair pathway, chromatin regulatory factors such as lysine (K)-specific demethylase 5A and ZMYND8 can further stabilize the enrichment of CHD4 at damaged sites by interacting with NuRD complex subunits (43). The aforementioned CRNs jointly participate in the dynamic remodeling of chromatin structure in the damaged region, thereby affecting the localization of DNA repair factors and choice of repair pathways (Fig. 2).

Abnormal CHD4 expression is closely related to insensitivity of tumors to radiotherapy (44) and chemotherapy (CT) (45), suggesting that it plays an important role in the development of tumor treatment resistance. In the context of DNA-damaging treatment, CHD4 can regulate chromatin structure to keep DDR-related genes ready to be rapidly activated, thereby enhancing tumor cells' ability to repair treatment-induced DNA damage. This effect is relatively typical in glioblastoma, where CHD4 maintains the expression of key HRR factors such as RAD51, thereby increasing tumor cell resistance to radiotherapy and DNA-damaging CT drugs (46). This phenomenon suggests that the treatment resistance mediated by CHD4 is not merely due to changes in a single repair factor but rather reflects CHD4′s regulation of the DNA repair transcriptional process's overall accessibility.

In addition to enhanced DNA repair ability, CHD4 can also participate in CT resistance by regulating pro-survival signaling pathways and drug efflux mechanisms. In GC, high CHD4 expression is closely related to tumor progression and CT resistance. CHD4 promotes the interaction between mitogen-activated protein kinase (MEK1/2) and extracellular signal-regulated kinase 1/2 (ERK1/2) and activates the MEK/ERK signaling pathway, thereby maintaining continuous phosphorylation of ERK and enhancing the proliferation and survival ability of tumor cells. Meanwhile, this pathway can also upregulate major vault protein expression, promote drug efflux, and reduce the intracellular concentration of CT drugs (for example, cisplatin), ultimately leading to CT resistance in GC cells (47). Similar drug efflux mechanisms can also be observed in ovarian cancer, where high CHD4 expression can upregulate that of multidrug resistance mutation 1 and enhance drug efflux ability, thereby reducing the accumulation of cisplatin in cells and leading to platinum-based CT resistance (48). These findings collectively indicate that CHD4 not only affects the DNA repair ability of tumor cells but may also expand drug resistance by remodeling the intracellular-drug disposition and survival signaling networks.

The effect of CHD4 on treatment response also extends to the level of cell cycle regulation. In BC, CHD4 forms the NuRD complex with HDAC1 and acts on the p21 promoter region, inhibiting the transcription and expression of p21 via chromatin remodeling and histone deacetylation (49). Since p21 is an important cell cycle inhibitor, such a decrease in its expression can promote cell cycle progression, making tumor cells more likely to bypass cell cycle checkpoints after DNA damage and thereby enhancing their resistance to CT drugs. This shows that CHD4-mediated treatment resistance not only depends on ‘repairing more damage’ but also involves the reshaping of cell cycle timing, enabling tumor cells to maintain a proliferative advantage under treatment pressure.

In addition to the intrinsic mechanisms of tumor cells, CHD4 can also affect the response to immunotherapy by regulating the tumor immune microenvironment. In microsatellite-stable CRC, CHD4 can recruit the histone methyltransferase euchromatic histone lysine methyltransferase 2 (EHMT2) to form a co-transcriptional inhibitory complex, thereby inhibiting the expression of galectin-7 (GAL7) and maintaining an immunosuppressive ‘cold-tumor’ microenvironment. Inhibition of EHMT2 can restore GAL7 expression and enhance Cluster of Differentiation 8⁺ (CD8⁺) T-cell-mediated antitumor immune responses, thereby increasing sensitivity to programmed cell death protein 1 inhibitor therapy (50). Pan-cancer data analysis further supports the important role of CHD4 in tumor treatment resistance. CHD4 promotes the development of genomic-instability characteristics via epigenetic regulation while shaping an immunosuppressive TME characterized by reduced CD8⁺ T-cell infiltration and increased immune escape (51). This suggests that the role of CHD4 extends beyond tumor cells themselves to the tumor immune system interactions on which treatment responses depend.

Notably, CHD4′s effect on treatment resistance does not always manifest in the same way but is shaped by specific genetic backgrounds. In BRCA1/2-deficient tumors, CHD4 deletion does not restore HRR ability but instead enhances replication fork stability by inhibiting meiotic recombination 11 homolog 1-mediated replication fork degradation, thereby increasing the resistance of tumor cells to cisplatin and PARP inhibitors (52). This phenomenon shows that the role of CHD4 cannot be simply summarized as ‘promoting repair’ or ‘inhibiting repair’; its deeper function may lie in regulating how tumor cells respond to replication and treatment stresses. Therefore, its role in tumor treatment resistance is obviously context dependent, and its biological consequences depend on the specifics of the genetic background, repair pathway state, and TME characteristics (Fig. 3).