| First Author | Mohan DR | Year | 2023 |
| Journal | Cancer Res | Volume | 83 |
| Issue | 13 | Pages | 2123-2141 |
| PubMed ID | 37129912 | Mgi Jnum | J:337744 |
| Mgi Id | MGI:7505708 | Doi | 10.1158/0008-5472.CAN-22-2712 |
| Citation | Mohan DR, et al. (2023) beta-Catenin-Driven Differentiation Is a Tissue-Specific Epigenetic Vulnerability in Adrenal Cancer. Cancer Res 83(13):2123-2141 |
| abstractText | Adrenocortical carcinoma (ACC) is a rare cancer in which tissue-specific differentiation is paradoxically associated with dismal outcomes. The differentiated ACC subtype CIMP-high is prevalent, incurable, and routinely fatal. CIMP-high ACC possess abnormal DNA methylation and frequent beta-catenin-activating mutations. Here, we demonstrated that ACC differentiation is maintained by a balance between nuclear, tissue-specific beta-catenin-containing complexes, and the epigenome. On chromatin, beta-catenin bound master adrenal transcription factor SF1 and hijacked the adrenocortical super-enhancer landscape to maintain differentiation in CIMP-high ACC; off chromatin, beta-catenin bound histone methyltransferase EZH2. SF1/beta-catenin and EZH2/beta-catenin complexes present in normal adrenals persisted through all phases of ACC evolution. Pharmacologic EZH2 inhibition in CIMP-high ACC expelled SF1/beta-catenin from chromatin and favored EZH2/beta-catenin assembly, erasing differentiation and restraining cancer growth in vitro and in vivo. These studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities. SIGNIFICANCE: Oncogenic beta-catenin can use tissue-specific partners to regulate cellular differentiation programs that can be reversed by epigenetic therapies, identifying epigenetic control of differentiation as a viable target for beta-catenin-driven cancers. |
