Abstract 1447: Histone demethylase JMJD1A regulates glutamine metabolism in prostate cancer

Abstract Epigenetic regulation plays a crucial role in the development and progression of prostate cancer. JMJD1A (also called KDM3A) promotes prostate cancer progression by upregulating gene expression through the removal of repressive H3K9 methylation marks. Here, we found a role for JMJD1A in the regulation of glutamine biosynthesis in prostate cancer cells. JMJD1A knockdown (KD) significantly reduced cellular glutamine levels and inhibited prostate cancer cell growth under glutamine-deprivation conditions. RNA-seq studies showed that JMJD1A KD reduced the levels of GLUL, a key enzyme in de novo glutamine synthesis. mRNA levels of JMJD1A and GLUL were positively correlated in human prostate cancer datasets. Re-expression of GLUL in JMJD1A-KD cells significantly restored cellular glutamine levels and partially rescued the growth defect of prostate cancer cells in glutamine-free growth media. Further, ChIP-seq studies showed that JMJD1A interacted with the methyltransferase EZH2 on the GLUL gene promoter, and JMJD1A/EZH2 cooperatively upregulated H3K27ac levels to promote GLUL expression. Our study revealed cooperation between JMJD1A and EZH2 in regulating gene expression and glutamine metabolism and supports the co-targeting of JMJD1A and EZH2 for potential prostate cancer therapy. Citation Format: Sudeep Khadka, Majid Pornour, Hee-Young Jeon, Arif Hussain, Jianfei Qi. Histone demethylase JMJD1A regulates glutamine metabolism in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1447.