Abstract 2726: A circadian regulator drives tumor lineage plasticity through chromatin bivalency resolution

Abstract Chromatin bivalency plays an important role in cell lineage specification during development. Cancer therapy resistance involves an extensive reprogramming of gene expression resulting in tumor lineage plasticity (LP). However, the underlying mechanisms are poorly understood. Rev-erb-alpha, a member of the nuclear receptor transcription factor family, plays a key role in regulation of circadian rhythm and metabolism primarily through repression of its target genes. We performed sequential ChIP-seq epigenome profiling of tumor tissues from the clinic and PDX models of prostate cancer and integrated analysis of tumor epigenome and transcriptome. We also treated the PDX models with small-molecule inhibitors of the receptor. We found that most of the tumor LP genes, including those in programs of neurodevelopment, neural signaling, stemness and EMT, are controlled by bivalent promoters with concurrent marking of H3K27me3 and H3K4me3. Our further studies revealed that the bivalent chromatin state resolves during the development of cancer therapy resistance. Interestingly, Rev-erb-alpha plays a critical role in promoting the bivalency resolution and activation of the LP programs. Its pharmacological targeting effectively reverses the bivalency resolution and diminishes the LP in anti-AR therapy-resistant tumors. Therefore, our study establishes that resolution of chromatin bivalency is a major epigenetic mechanism of tumor LP and demonstrates that therapeutic targeting of Rev-erb-alpha represents a novel treatment of advanced prostate cancer. This work was supported by NIH and UC Davis comprehensive cancer center and U.S. Department of Defense. Citation Format: Yatian Yang, Xiong zhang, hongye zou, Eva Corey, Ronald M. Evans, Amina Zoubeidi, Hongwu Chen. A circadian regulator drives tumor lineage plasticity through chromatin bivalency resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2726.