SCIENtIFIC REPORTS | (2018) 8:4505 | DOI:10.1038/s41598-018-22771-2
Alpha-oxoglutarate inhibits the
proliferation of immortalized
normal bladder epithelial cells via
an epigenetic switch involving
, Nicole Gull
, Austin Yeon
, Eunho Cho
, Jooeun Bae
, Hyun Seok Yoon
, Hana Yoon
, Minjung Kim
, Benjamin P. Berman
& Jayoung Kim
Interstitial cystitis (IC) is a chronic urinary tract disease that is characterized by unpleasant
sensations, such as persistent pelvic pain, in the absence of infection or other identiable causes. We
previously performed comprehensive metabolomics proling of urine samples from IC patients using
nuclear magnetic resonance and gas-chromatography/mass spectrometry and found that urinary
α-oxoglutarate (α-OG), was signicantly elevated. α-OG, a tricarboxylic acid (TCA) cycle intermediate,
reportedly functions to suppress the proliferation of immortalized normal human bladder epithelial
cells. Here, we identied AT-rich interactive domain 1 A (ARID1A), a key chromatin remodeler, as being
hypomethylated and upregulated by α-OG treatment. This was done through EPIC DNA methylation
proling and subsequent biochemical approaches, including quantitative RT-PCR and western blot
analyses. Furthermore, we found that α-OG almost completely suppresses ten-eleven translocation
(TET) activity, but does not aect DNA methyltransferase (DNMT) activity. Altogether, our studies
reveal the potential role of α-OG in epigenetic remodeling through its eects on ARID1A and TET
expression in the bladder. This may provide a new possible therapeutic strategy in treating IC.
Urine is a critical biological uid that is ltered through the kidneys and stored in the bladder. It contains the
expression of many metabolites, such as urea (from amino acid metabolism), inorganic salts (chloride, sodium,
and potassium), creatinine, ammonia, organic acids, various water-soluble toxins, and pigmented products
from hemoglobin breakdown. Because urination is also the primary route through which the body eliminates
water-soluble waste and extra unnecessary products, urine has long been considered as an expendable composite.
However, more recently, urine has been acknowledged as an uninvestigated biomarker source with great poten-
tial use for disease diagnosis. While previous studies of urine have mainly focused on its chemical composition,
new focus is being placed on its metabolic properties as indicative sources for medical disorders. Although the
complexity of sources within metabolites creates many obstacles in urine analysis, progress in the eld has been
promising. Urine analysis could prove to be tremendously benecial
Interstitial cystitis/bladder pain syndrome (IC/BPS, hereaer IC) is a debilitating urological dysfunction that
presents itself as a constellation of symptoms, including bladder pain, urinary urgency, frequency, nocturia, and
small voided volumes, in the absence of other identiable etiologies
. e prevalence of IC in the United States
is 3–6% in women and 2–4% in men
. IC patients experience substantial decline in physical activity, social
Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los
Angeles, California, USA.
University of California Los Angeles, Los Angeles, CA, USA.
Department of Urology,
School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
Department of Molecular Oncology,
Mott Cancer Center, Tampa, Florida, USA.
Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical
Center, Los Angeles, CA, USA.
Department of Urology, Ga Cheon University College of Medicine, Incheon, Republic
of Korea. Muhammad Shahid and Nicole Gull contributed equally to this work. Correspondence and requests for
materials should be addressed to J.K. (email: Jayoung.Kim@cshs.org)
Received: 28 November 2017
Accepted: 23 February 2018
Published: xx xx xxxx
Correction: Author Correction