Role of KDM3A and EZH2 in Regulation of Glutamine Metabolism and Prostate Cancer Progression

Abstract

Epigenetic dysregulation is a hallmark of various cancers, including prostate cancer (PCa), and contributes to disease development and progression. KDM3A is a histone 3 lysine 9 (H3K9) demethylase that removes the repressive H3K9 methylation marks and promotes gene expression. EZH2, a catalytic subunit of Polycomb Repressive Complex 2 (PRC2), induces H3K27 trimethylation repressive marks to inhibit gene expression (canonical activity). In contrast to the repressive role of PRC2, we found that it interacts with KDM3A to promote transcription of selective genes such as GLUL (non-canonical activity). GLUL catalyzes de-novo glutamine synthesis that converts ammonia and glutamate to glutamine. Glutamine metabolism yields α-Ketoglutarate, an essential molecule for the tricarboxylic acid cycle (TCA). Additionally, it plays a crucial role in the synthesis of various macromolecules, including nucleotides, proteins, and hexosamine. Cancer cells including PCa cells are mostly addicted to glutamine and switch to glutamine metabolism for proliferation and survival. We aim to investigate the mechanism of transcriptional regulation of GLUL and glutamine metabolism in PCa progression due to KDM3A and PRC2 complex interaction, primarily focusing on the non-canonical role of PRC2 complex