β-catenin programs a tissue-specific epigenetic vulnerability in aggressive adrenocortical carcinoma

Mohan, D. R.; Borges, K. S.; Finco, I.; LaPensee, C. R.; Rege, J.; Solon, A. L.; Little, D. W.; Else, T.; Almeida, M. Q.; Dang, D.; Haggerty-Skeans, J.; Apfelbaum, A. A.; Vinco, M.; Wakamatsu, A.; Mariani, B. M. P.; Amorin, L.; Latronico, A. C.; Mendonca, B. B.; Zerbini, M. C. N.; Lawlor, E. R.; Ohi, R.; Auchus, R. J.; Rainey, W. E.; Marie, S. K. N.; Giordano, T. J.; Venneti, S.; Fragoso, M. C. B. V.; Breault, D. T.; Lerario, A. M.; Hammer, G. D.

doi:10.1101/2022.07.02.497654

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bioRxiv · 10.1101/2022.07.02.497654

β-catenin programs a tissue-specific epigenetic vulnerability in aggressive adrenocortical carcinoma

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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 {beta}-catenin activating mutations. Here, we demonstrate that ACC differentiation is maintained by a balance between nuclear, tissue-specific {beta}-catenin-containing complexes and the epigenome. On chromatin, {beta}-catenin binds master adrenal transcription factor SF1 and hijacks the adrenocortical super-enhancer landscape to maintain differentiation. Off chromatin, {beta}-catenin binds histone methyltransferase EZH2, which is redistributed by the CIMP-high DNA methylation signature. SF1/{beta}-catenin and EZH2/{beta}-catenin complexes exist in normal adrenals and are selected for through all phases of ACC evolution. Pharmacologic EZH2 inhibition in CIMP-high ACC favors EZH2/{beta}-catenin assembly and purges SF1/{beta}-catenin from chromatin, erasing differentiation and restraining cancer growth in vitro and in vivo. Our studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities.

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Mohan, D. R., Borges, K. S., Finco, I., LaPensee, C. R., Rege, J., Solon, A. L., Little, D. W., Else, T., Almeida, M. Q., Dang, D., Haggerty-Skeans, J., Apfelbaum, A. A., Vinco, M., Wakamatsu, A., Mariani, B. M. P., Amorin, L., Latronico, A. C., Mendonca, B. B., Zerbini, M. C. N., Lawlor, E. R., Ohi, R., Auchus, R. J., Rainey, W. E., Marie, S. K. N., Giordano, T. J., Venneti, S., Fragoso, M. C. B. V., Breault, D. T., Lerario, A. M., Hammer, G. D.. 2022-07-04. β-catenin programs a tissue-specific epigenetic vulnerability in aggressive adrenocortical carcinoma. https://doi.org/10.1101/2022.07.02.497654

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