Abstract 2415: H2A monoubiquitination links glucose availability to epigenetic regulation of the endoplasmic reticulum stress induced cell death in cancer

Introduction Epigenetic regulation of gene transcription coordinates with nutrient availability, although the underlying mechanisms remain incompletely understood. Histone 2A monoubiquitination at lysine 119 (H2Aub), catalyzed mainly by its writer polycomb repressive complex 1 (PRC1), is a histone modification that has been associated with transcriptional repression. Initially, we found glucose withdrawal dramatically decreased H2Aub levels in multiple cancer cell lines. Next, we sought to study the role of H2Aub and H2Aub-associated transcriptional network in tumor cells while modulating glucose availability. Experimental design To determine the genes regulated by H2Aub upon glucose deprivation, H2Aub ChIP-seq and RNA-seq analyses were performed in UMRC6 kidney cancer cells with or without glucose. To identify the biological processes associated with the genes identified in our genome-wide analyses, we used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Results We found that glucose starvation suppresses histone 2A K119 monoubiquitination (H2Aub), a histone modification that correlates with gene repression. Mechanistically, glucose starvation suppressed H2Aub levels independently of energy stress-mediated AMPK activation and likely acts through reactive oxygen species (ROS)-mediated inhibition of BMI1, an integral component of polycomb repressive complex 1 (PRC1) that catalyzes H2Aub on chromatin. Integrated transcriptomic and epigenomic analyses linked glucose starvation-mediated H2Aub repression to the activation of genes involved in the endoplasmic reticulum (ER) stress response. We further showed that this epigenetic mechanism has a role in glucose starvation-induced cell death. In addition, pharmacologic inhibition of glucose transporter 1 (GLUT1) and PRC1 synergistically promoted ER stress and suppressed tumor growth in vitro and in vivo. Conclusion Our study suggests a model in which glucose starvation inhibits PRC1 function potentially through glucose starvation-induced BMI phosphorylation and thereby decreases H2Aub levels, which leads to the de-repression of ER stress gene expression and contributes to the ER stress response and glucose starvation-induced cell death. Together, our results reveal a hitherto unrecognized epigenetic mechanism coupling glucose availability to the ER stress response. Citation Format: Yilei Zhang, Jiejun Shi, Zhenna Xiao, Guang Lei, Xiaoguang Liu, Hyemin Lee, Pranavi Koppula, Weijie Cheng, Chao Mao, Li Zhuang, Li Ma, Wei Li, Boyi Gan. H2A monoubiquitination links glucose availability to epigenetic regulation of the endoplasmic reticulum stress induced cell death in cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2415.