CHD4 Orchestrates Chromatin Remodeling to Activate the c‐Myc Signaling Pathway in Cancer Pathogenesis

ABSTRACT Chromatin abnormalities are a hallmark of cancer, but the role of the chromatin remodeler CHD4 in multiple myeloma (MM) remains unclear. This study aims to elucidate how CHD4 drives MM progression and to explore targeted therapeutic strategies. Using CHD4 overexpression and knockdown models in MM cell lines, we found that elevated CHD4 correlates with poor prognosis and increased proliferation. Mechanistically, we performed chromatin profiling and luciferase reporter assays to show that the ATPase domain of CHD4 resolves G‐quadruplex structures in the c‐Myc promoter, thereby enhancing chromatin accessibility. Co‐immunoprecipitation (Co‐IP) and chromatin immunoprecipitation (ChIP) further revealed that CHD4 stabilizes c‐Myc activity through liquid‐liquid phase separation (LLPS), increasing c‐Myc chromatin retention and promoter occupancy. To identify CHD4 targets, we integrated RNA‐seq with chromatin profiling. Structure‐based drug design identified luteolin 7‐O‐glucuronide (LUT) as an inhibitor of CHD4's ATPase domain and idarubicin (IDA) as an inhibitor of its chromatin‐interaction domain; combination treatment synergistically suppressed MM proliferation in adoptive B‐cell transfer, xenograft, and 5TMM3VT mouse models. Our findings establish CHD4 as a key oncogenic driver in MM and propose a LUT/IDA combination as a precision medicine strategy, advancing the understanding of chromatin remodeling in cancer.