Abstract 7106: Distinct functions of EHMT1 and EHMT2 in cancer chemotherapy and immunotherapy

Abstract EHTM1 (GLP) and EHMT2 (G9a) are closely related protein lysine methyltransferases often thought to function together as a heterodimer to methylate histone H3 and non-histone substrates in diverse cellular processes including transcriptional regulation, genome methylation, and DNA repair. Here we show that EHMT1/2 inhibitors cause DNA replication stress, accumulation of single-stranded replication gaps, increased expression of STING, emergence of cytosolic DNA, and activation of the cGAS-STING pathway. Remarkably, EHMT1/2 inhibition strongly potentiates the efficacy of alkylating chemotherapy and anti-PD-1 immunotherapy in mouse models of tripe negative breast cancer. Mechanistically, the effects of EHMT inhibition on DNA replication and alkylating agent sensitivity are largely caused by the loss of EHMT1-mediated methylation of DNA ligase I (LIG1), whereas the elevated STING expression is, at least part, caused by its promoter demethylation. Moreover, depletion of EHMT2, and not EHMT1, leads to STING induction, which is correlated with more complete demethylation of the STING1 promoter. On the other hand, depletion of EHMT1, and not EHMT2, results in cytosolic DNA accumulation, which presumably activates the cGAS-STING pathway. These results reveal distinct functions of the two EHMT paralogs and provide enlightening paradigms and corresponding molecular basis for combination therapies involving alkylating agents and immune checkpoint inhibitors. Citation Format: Zhihua Kang, Pan Fu, Hui Ma, Tao Li, Kevin Lu, Juan Liu, Vasudeva Ginjala, Peter Romanienko, Zhaohui Feng, Ming Guan, Shridar Ganesan, Bing Xia. Distinct functions of EHMT1 and EHMT2 in cancer chemotherapy and immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7106.