β-Catenin-Driven Differentiation Is a Tissue-Specific Epigenetic Vulnerability in Adrenal Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 83; no. 13; pp. 2123 - 2141
• Main Authors: Mohan, Dipika R, Borges, Kleiton S, Finco, Isabella, LaPensee, Christopher R, Rege, Juilee, Solon, April L, Little, Donald W, Else, Tobias, Almeida, Madson Q, Dang, Derek, Haggerty-Skeans, James, Apfelbaum, April A, Vinco, Michelle, Wakamatsu, Alda, Mariani, Beatriz M P, Amorim, Larissa Costa, Latronico, Ana Claudia, Mendonca, Berenice B, Zerbini, Maria Claudia N, Lawlor, Elizabeth R, Ohi, Ryoma, Auchus, Richard J, Rainey, William E, Marie, Suely K N, Giordano, Thomas J, Venneti, Sriram, Fragoso, Maria Candida Barisson Villares, Breault, David T, Lerario, Antonio Marcondes, Hammer, Gary D
• Format: Journal Article
• Language: English
• Published: United States 05.07.2023
• Subjects: Adrenal Cortex Neoplasms - genetics; Adrenal Cortex Neoplasms - pathology; Adrenocortical Carcinoma - genetics; Adrenocortical Carcinoma - metabolism; Adrenocortical Carcinoma - pathology; beta Catenin - genetics; beta Catenin - metabolism; Chromatin - genetics; Epigenesis, Genetic; Humans
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-22-2712

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 β-catenin-activating mutations. Here, we demonstrated that ACC differentiation is maintained by a balance between nuclear, tissue-specific β-catenin-containing complexes, and the epigenome. On chromatin, β-catenin bound master adrenal transcription factor SF1 and hijacked the adrenocortical super-enhancer landscape to maintain differentiation in CIMP-high ACC; off chromatin, β-catenin bound histone methyltransferase EZH2. SF1/β-catenin and EZH2/β-catenin complexes present in normal adrenals persisted through all phases of ACC evolution. Pharmacologic EZH2 inhibition in CIMP-high ACC expelled SF1/β-catenin from chromatin and favored EZH2/β-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. Oncogenic β-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 β-catenin-driven cancers.