An epigenetic switch on ARID1A chromatin remodeler by alpha‐oxoglutarate activates the antiproliferative axis in interstitial cystitis

Abstract

Interstitial cystitis (IC) is a chronic urinary tract disease that is characterized by unpleasant sensations, such as chronic pelvic pain and various other symptoms, in the absence of infection or other identifiable causes. We previously performed comprehensive metabolomics profiling of urine in IC patients using nuclear magnetic resonance and gas-chromatography/mass spectrometry and found that urinary α-oxoglutarate was significantly elevated. α-oxoglutarate (α-OG), the tricarboxylic acid (TCA) cycle intermediate, reportedly functions to suppress the proliferation of normal human bladder epithelial cells. Here, we identified AT-rich interactive domain 1A (ARID1A), a key chromatin remodeler, as being hypomethylated and upregulated by 2-oxoglutarate treatment. This was done through EPIC DNA methylation profiling and subsequent biochemical approaches, including quantitative RT-PCR and western blot analyses. Furthermore, we found that α-oxoglutarate almost completely suppresses ten-eleven translation (TET) activity, but does not affect DNA methyltransferase (DNMT) activity. DNMT inhibition in our IC rat models did not limit IC-associated symptoms or cytokine production. Altogether, our studies reveal the potential role of α-OG in epigenetic remodeling through its effects on AR1DA and TET in the bladder, which could provide a promising therapeutic strategy for IC treatment. Support or Funding Information The authors acknowledge support from National Institutes of Health grants (1U01DK103260, 1R01DK100974, U24 DK097154, NIH NCATS UCLA CTSI UL1TR000124), Department of Defense grants (W81XWH-15-1-0415), Centers for Disease Controls and Prevention (1U01DP006079), IMAGINE NO IC Research Grant, the Steven Spielberg Discovery Fund in Prostate Cancer Research Career Development Award, the U.S.-Egypt Science and Technology Development Fund by the National Academies of Sciences, Engineering, and Medicine (to J.K.). J.K. is former recipient of Interstitial Cystitis Association Pilot Grant, a Fishbein Family IC Research Grant, New York Academy of Medicine, and Boston Children's Hospital Faculty Development. The funders had no role in the design, data collection and analysis, decision to publish or preparation of the manuscript. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.