Abstract 343: Cooperation between PRMT1 and PRMT6 drives lung cancer health disparities among Black/African American men

Abstract

Abstract Non-Hispanic Black/African American (Black/AA) men in the United States have disproportionally higher incidence and mortality rates of lung cancer compared to non-Hispanic White (NHW) men. Molecular determinants including biological and genetic factors are believed to play critical roles in driving disparities. Yet, several recent large-scale genomic studies fail to identify significant somatic differences in lung cancer driver genes contributing to observed disparities between Black/AA and NHW groups. These findings suggest that epigenetic mechanisms may contribute to lung cancer disparities in Black/AA men. Arginine methylation is a post-translational modification catalyzed by protein arginine methyltransferases (PRMTs) that has gained considerable interest as many cancer types display elevated expression of PRMTs correlating with poor prognosis. Here, we observed a significant difference in the expression levels of PRMT6 between Black/AA men vs. NHW men with non-small cell lung cancer (NSCLC) that may contribute to cancer health disparities. To uncover the molecular mechanism by which PRMT6 drives lung cancer, we performed co-immunoprecipitation, protein arginine methylation, and cell proliferation assays using several NSCLC cell lines. We demonstrated that PRMT6 formed a heteromer complex with PRMT1 and disruption of the complex with a competitive peptide inhibitor significantly reduced cancer cell proliferation. We further showed that PRMT1/PRMT6 heteromer complex recruited and catalyzed arginine methylation of interleukin enhancer-binding factor 2 (ILF2). Disrupting heteromer complex formation leaded to a significant reduction of ILF2 methylation and expression. Finally, downregulation of ILF2 expression reduced the positive effects of PRMT1/PRMT6 complex on cell proliferation. Our findings demonstrate the significant functionality of PRMT1/PRMT6 heteromer complex to positively regulate ILF2 expression that is essential for cancer cell proliferation. Furthermore, we uncover a category of substrates for this complex providing the new insights for more potential therapeutic targets that may set the stage for developing new alternative approach to PRMT inhibition. This approach would potentially allow the ability to overcome the current limitations of PRMT1 or PRMT6 inhibitors, thereby opening up new horizons for efficacious PRMT1/PRMT6-targeted agents that are expected to eliminate lung cancer health disparities in Black/AA men. Citation Format: Ching-Yi Chen, Pei-Ying Wu, Michelle Van Scoyk, Stephanie A. Simko, Chu-Fang Chou, Robert A. Winn. Cooperation between PRMT1 and PRMT6 drives lung cancer health disparities among Black/African American men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 343.