Abstract LB192: Sulforaphane suppression of Prmt5 and Mep50 function suppresses the mesothelioma cancer stem cell phenotype

Abstract

Abstract Mesothelioma is an aggressive and fatal cancer of the mesothelial lining which is caused by asbestos exposure. The current treatment strategy is surgical resection followed by chemotherapy, but this is marginally successful and leads to drug resistant and recurrent disease. Mesothelioma cancer stem cells (MCS cells) comprise an important subpopulation of highly aggressive mesothelioma tumor cells that maintain tumor formation and mediate drug resistance. Our goal is to identify proteins that maintain the MCS cell and non-stem cancer cell survival as therapy targets. Protein arginine methyltransferase 5 (PRMT5) functions with the MEP50 cofactor to catalyze symmetric dimethylation of specific arginine resides in histones 3 and 4 to silence tumor suppressor gene expression and enhance cancer cell survival. Our studies show that loss of PRMT5 or MEP50 reduces H4R3me2s formation in MCS cells and that this is associated with a reduction in MCS cell spheroid formation, invasion and migration. Additionally, treatment with sulforaphane (SFN), a promising diet-derived cancer prevention and therapy agent, reduces PRMT5/MEP50 level and H4R3me2s formation, and suppresses the MCS cell phenotype. Moreover, forced expression of PRMT5/MEP50 antagonizes SFN suppression of the MCS cell phenotype, suggesting that loss of PRMT5/MEP50 is required for SFN action. SFN treatment also markedly reduces tumor formation and this is associated with reduced PRMT5/MEP50 expression and H4R3me2s formation. These findings suggest that SFN suppresses PRMT5/MEP50 function to attenuate the MCS cell phenotype and reduce tumor formation, and that SFN may be a useful mesothelioma prevention and therapy agent. Citation Format: Geraldine C. Ezeka, Gautam Adhikary, Sivaveera Kandasamy, Joseph Friedberg, Richard Eckert. Sulforaphane suppression of Prmt5 and Mep50 function suppresses the mesothelioma cancer stem cell phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB192.