CHD4 epigenetically coordinates genomic instability and immunosuppression to drive pan-cancer progression and confer HDAC inhibitor sensitivity.

Chromodomain Helicase DNA-Binding Protein 4 (CHD4), the core ATPase subunit of the nucleosome remodeling and deacetylation (NuRD) complex, is a key epigenetic regulator. However, a systematic pan-cancer perspective on its functions, particularly its coordinated regulation of genomic stability alongside the tumor immune microenvironment, remains lacking. This study performed an integrated multi-omics analysis using data from The Cancer Genome Atlas (TCGA) and complementary genomic databases. This included systematic profiling of CHD4 expression, genomic alterations, and clinical associations across cancers. We investigated its correlations with markers of genomic instability, immune cell infiltration, and therapy response. Functional enrichment and pharmacogenomic analyses were conducted, supported by in vitro validation in osteosarcoma models. CHD4 was frequently upregulated across multiple cancer types, and its elevated expression was associated with poorer patient prognosis in several malignancies. Pan-cancer analysis revealed that high CHD4 expression correlated significantly with markers of genomic instability, such as homologous recombination deficiency (HRD) and loss of heterozygosity (LOH), and concurrently with an immunosuppressive tumor microenvironment—characterized by reduced CD8 + T cell infiltration and elevated expression of immune checkpoint molecules. Mechanistically, CHD4 expression was closely linked to core components of the NuRD complex, including HDAC1 and HDAC2, suggesting its involvement in chromatin compaction and transcriptional regulation associated with these phenotypes. Furthermore, tumors exhibiting high CHD4 expression showed increased sensitivity to histone deacetylase (HDAC) inhibitors, including vorinostat and panobinostat. This study establishes CHD4 as a pan-cancer epigenetic regulator whose expression is linked to both genomic instability and immune suppression. Furthermore, CHD4 shows promise as a predictive biomarker for sensitivity to HDAC inhibitors, highlighting its potential as a biomarker for guiding epigenetics-based therapeutic strategies.