β-Catenin–Driven Differentiation Is a Tissue-Specific Epigenetic Vulnerability in Adrenal Cancer
Dipika R. Mohan, Kleiton Silva Borges, Isabella Finco, Christopher R. LaPensee, Juilee Rege, April L. Solon, Donald W. Little, Tobias Else, Madson Q. Almeida, Derek Dang, James Haggerty-Skeans, April A. Apfelbaum, Michelle Vinco, Alda Wakamatsu, Beatriz M. P. Mariani, Larissa Costa Amorim, Ana Cláudia Latronico, Berenice B. Mendonça, Maria Cláudia Nogueira Zerbini, Elizabeth R. Lawlor, Ryoma Ohi, Richard J. Auchus, William E. Rainey, Suely Kazue Nagahashi Marie, Thomas J. Giordano, Sriram Venneti, Maria Candida Barisson Villares Fragoso, David T. Breault, Antônio Marcondes Lerário, Gary D. Hammer
Abstract
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. SIGNIFICANCE: 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.