TY - JOUR
T1 - DNA methylation patterns in bladder tumors of African American patients point to distinct alterations in xenobiotic metabolism
AU - Vantaku, Venkatrao
AU - Amara, Chandra Sekhar
AU - Piyarathna, Danthasinghe Waduge Badrajee
AU - Donepudi, Sri Ramya
AU - Ambati, Chandrashekar R.
AU - Putluri, Vasanta
AU - Tang, Wei
AU - Rajapakshe, Kimal
AU - Estecio, Marcos Roberto
AU - Terris, Martha K.
AU - Castro, Patricia D.
AU - Ittmann, Michael M.
AU - Williams, Stephen B.
AU - Lerner, Seth P.
AU - Sreekumar, Arun
AU - Bollag, Roni
AU - Coarfa, Cristian
AU - Kornberg, Michael D.
AU - Lotan, Yair
AU - Ambs, Stefan
AU - Putluri, Nagireddy
N1 - Funding Information:
This research was supported by American Cancer Society (ACS) Award (127430-RSG-15-105-01-CNE to N.P., NIH/NCI R01CA220297 to N.P., NIH/NCI R01CA216426 to N.P. and NIH/NCI U01 CA167234 to A.S.K.). This project was also supported by the Agilent Technologies Center of Excellence (COE) and National Institute of Health (NIH) (P30 CA125123), CPRIT Proteomics and Metabolomics Core Facility (RP170005 to N.P.), and Dan L. Duncan Cancer Center. P.D.C. and M.M.I., were supported by Human Tissue Acquisition and Pathology at Baylor College of Medicine with funding from National Cancer Institute (NCI) (P30 CA125123). The Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health (NIH) (P30 CA142543 09).
Funding Information:
1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA, 2Dan L. Duncan Cancer Center, Advanced Technology Core, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA, 3Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA, 4Center for Cancer Epigenetics, Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA, 5Department of Surgery: Urology, Augusta University, Augusta, GA, USA, 6Human tissue acquisition and pathology shared source, Baylor College of Medicine, Houston, TX, USA, 7Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA, 8Michael E. DeBakey Department of Veterans Affairs Medical Center, Houston, TX, USA, 9Division of Urology, Department of Surgery, The University of Texas Medical Branch, Galveston, TX, USA, 10Scott Department of Urology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA, 11Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA, 12Department of Pathology, Augusta University, Augusta, GA, USA, 13Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA, and 14Department of Urology, University of Texas Southwestern, Dallas, TX, USA
Publisher Copyright:
© 2019 The Author(s). Published by Oxford University Press. All rights reserved.
PY - 2019/11/25
Y1 - 2019/11/25
N2 - Racial/ethnic disparities have a significant impact on bladder cancer outcomes with African American patients demonstrating inferior survival over European-American patients. We hypothesized that epigenetic difference in methylation of tumor DNA is an underlying cause of this survival health disparity. We analyzed bladder tumors from African American and European-American patients using reduced representation bisulfite sequencing (RRBS) to annotate differentially methylated DNA regions. Liquid chromatography-mass spectrometry (LC-MS/MS) based metabolomics and flux studies were performed to examine metabolic pathways that showed significant association to the discovered DNA methylation patterns. RRBS analysis showed frequent hypermethylated CpG islands in African American patients. Further analysis showed that these hypermethylated CpG islands in patients are commonly located in the promoter regions of xenobiotic enzymes that are involved in bladder cancer progression. On follow-up, LC-MS/MS revealed accumulation of glucuronic acid, S-adenosylhomocysteine, and a decrease in S-adenosylmethionine, corroborating findings from the RRBS and mRNA expression analysis indicating increased glucuronidation and methylation capacities in African American patients. Flux analysis experiments with 13C-labeled glucose in cultured African American bladder cancer cells confirmed these findings. Collectively, our studies revealed robust differences in methylation-related metabolism and expression of enzymes regulating xenobiotic metabolism in African American patients indicate that race/ethnic differences in tumor biology may exist in bladder cancer.
AB - Racial/ethnic disparities have a significant impact on bladder cancer outcomes with African American patients demonstrating inferior survival over European-American patients. We hypothesized that epigenetic difference in methylation of tumor DNA is an underlying cause of this survival health disparity. We analyzed bladder tumors from African American and European-American patients using reduced representation bisulfite sequencing (RRBS) to annotate differentially methylated DNA regions. Liquid chromatography-mass spectrometry (LC-MS/MS) based metabolomics and flux studies were performed to examine metabolic pathways that showed significant association to the discovered DNA methylation patterns. RRBS analysis showed frequent hypermethylated CpG islands in African American patients. Further analysis showed that these hypermethylated CpG islands in patients are commonly located in the promoter regions of xenobiotic enzymes that are involved in bladder cancer progression. On follow-up, LC-MS/MS revealed accumulation of glucuronic acid, S-adenosylhomocysteine, and a decrease in S-adenosylmethionine, corroborating findings from the RRBS and mRNA expression analysis indicating increased glucuronidation and methylation capacities in African American patients. Flux analysis experiments with 13C-labeled glucose in cultured African American bladder cancer cells confirmed these findings. Collectively, our studies revealed robust differences in methylation-related metabolism and expression of enzymes regulating xenobiotic metabolism in African American patients indicate that race/ethnic differences in tumor biology may exist in bladder cancer.
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U2 - 10.1093/carcin/bgz128
DO - 10.1093/carcin/bgz128
M3 - Article
C2 - 31284295
AN - SCOPUS:85075814409
SN - 0143-3334
VL - 40
SP - 1332
EP - 1340
JO - Carcinogenesis
JF - Carcinogenesis
IS - 11
ER -