DNA methylation patterns in bladder tumors of African American patients point to distinct alterations in xenobiotic metabolism.
Black or African American
/ genetics
Chromatography, Liquid
CpG Islands
DNA Methylation
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Glucuronic Acid
/ analysis
Humans
Inactivation, Metabolic
/ genetics
Metabolomics
Promoter Regions, Genetic
S-Adenosylhomocysteine
/ analysis
S-Adenosylmethionine
/ analysis
Tandem Mass Spectrometry
Urinary Bladder Neoplasms
/ genetics
White People
/ genetics
Journal
Carcinogenesis
ISSN: 1460-2180
Titre abrégé: Carcinogenesis
Pays: England
ID NLM: 8008055
Informations de publication
Date de publication:
25 11 2019
25 11 2019
Historique:
received:
03
02
2019
revised:
23
05
2019
accepted:
07
07
2019
pubmed:
10
7
2019
medline:
28
5
2020
entrez:
9
7
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31284295
pii: 5529845
doi: 10.1093/carcin/bgz128
pmc: PMC6875901
doi:
Substances chimiques
S-Adenosylmethionine
7LP2MPO46S
Glucuronic Acid
8A5D83Q4RW
S-Adenosylhomocysteine
979-92-0
Types de publication
Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1332-1340Subventions
Organisme : NCI NIH HHS
ID : R01 CA220297
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA216426
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA167234
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA142543
Pays : United States
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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