RF21 | PSAT76 Epigenetic Programs Stabilize a Differentiated Cell State Required for Sustained Proliferation in Adrenocortical Carcinoma

Adrenocortical carcinoma (ACC) is a rare, aggressive, and poorly understood cancer of the adrenal cortex. Abnormal epigenetic patterning is a major predictor of dismal disease outcomes. Patients with genome-wide CpG island hypermethylation (CIMP-high) experience rapidly recurrent and routinely fatal disease. A deeper understanding of how epigenetic programs coordinate tumorigenesis is essential to develop improved medical therapies. We identify that DNA hypermethylation is directed to targets of a histone modifying complex, PRC2, suggesting cross-talk between DNA and histone methylation in CIMP-high ACC. In contrast to our expectations, we discovered that DNA methylation and PRC2-directed histone methylation are mutually exclusive. Additionally, we identified that EZH2 (a canonical member of the PRC2) forms a separate complex with tissue-specific proteins to coordinate sustained proliferation and steroidogenic differentiation in vitro and in vivo. These complexes persist through advanced stages of human malignancy and are conserved in mouse models of adrenal carcinogenesis. Taken together, our studies illustrate how CpG island hypermethylation exposes a pharmacologically targetable tissue-specific therapeutic vulnerability, and stabilizes a differentiation state required for sustained proliferation. Ultimately, we hope this work illuminates novel strategies for tissue-specific disruption of the aberrant epigenetic wiring supporting this devastating disease. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 1:24 p.m. - 1:30 p.m.