Profiling of RUVBL2-Induced Transcriptome Alterations Highlights a Critical Role for Chromatin Remodeling in Ovarian...

Cancerous transcriptome alterations in carcinoma cells could be originated from either genetic copy number changes or epigenetic reprogramming. Ovarian cancer (OV) is the most malignant gynecologic tumor, known for high aneuploidy with robust copy number alterations. However, low aneuploidy ovarian tumors are also frequently found, indicating an essential contribution of epigenetic factors during tumorigenesis and cancer development. Chromatin remodeling modulates the transcriptome epigenetically in a variety of cancer types, but its role in OV is still unclear. Hence, we investigated a cohort of 102 OV patients, analyzed transcriptomic and clinical data from public databases, and performed cellular experiments. We found that RUVBL2, a subunit of the INO80 complex, functions as the key oncogenic chromatin remodeler in OV. RUVBL2 is upregulated in tumors, particularly in low-aneuploidy cases, and is associated with poor prognosis. RUVBL2 drives nucleosome dynamics and elevates chromatin accessibility selectively at promoter regions. The landscape of RUVBL2-dependent modulation of chromatin accessibility and the transcriptome exhibits activation of various transcription factors, especially the AP-1 family, and upregulation of a series of key genes, including CDKN3, MYBL2, and ZNF144, resulting in mediation of cell cycle and Hippo signaling pathway to promote DNA synthesis and cell proliferation. Hence, RUVBL2-dependent chromatin remodeling plays a key role in oncogenic reprogramming of the transcriptome in OV. These findings provide novel insights into the molecular etiology of OV and disclose potential biomarkers and drug targets.