Journal article
Metformin pharmacogenomics: a genome-wide association study to identify genetic and epigenetic biomarkers involved in metformin anticancer response using human lymphoblastoid cell lines
Human molecular genetics, Vol.25(21), pp.4819-4834
11/01/2016
DOI: 10.1093/hmg/ddw301
PMCID: PMC6078562
PMID: 28173075
Abstract
Metformin is currently considered as a promising anticancer agent in addition to its anti-diabetic effect. To better individualize metformin therapy and explore novel molecular mechanisms in cancer treatment, we conducted a pharmacogenomic study using 266 lymphoblastoid cell lines (LCLs). Metformin cytotoxicity assay was performed using the MTS assay. Genome-wide association (GWA) analyses were performed in LCLs using 1.3 million SNPs, 485k DNA methylation probes, 54k mRNA expression probe sets, and metformin cytotoxicity (IC50s). Top candidate genes were functionally validated using siRNA screening, followed by MTS assay in breast cancer cell lines. Further study of one top candidate, STUB1, was performed to elucidate the mechanisms by which STUB1 might contribute to metformin action. GWA analyses in LCLs identified 198 mRNA expression probe sets, 12 SNP loci, and 5 DNA methylation loci associated with metformin IC50 with P-values <10(-4) or <10(-5). Integrated SNP/methylation loci-expression-IC50 analyses found 3 SNP loci or 5 DNA methylation loci associated with metformin IC50 through trans-regulation of expression of 11 or 26 genes with P-value <10(-4). Functional validation of top 61 candidate genes in 4 IPA networks indicated down regulation of 14 genes significantly altered metformin sensitivity in two breast cancer cell lines. Mechanistic studies revealed that the E3 ubiquitin ligase, STUB1, could influence metformin response by facilitating proteasome-mediated degradation of cyclin A. GWAS using a genomic data-enriched LCL model system, together with functional and mechanistic studies using cancer cell lines, help us to identify novel genetic and epigenetic biomarkers involved in metformin anticancer response.
Details
- Title: Subtitle
- Metformin pharmacogenomics: a genome-wide association study to identify genetic and epigenetic biomarkers involved in metformin anticancer response using human lymphoblastoid cell lines
- Creators
- Nifang Niu - Mayo Clin, Coll Med, Dept Mol Pharmacol & Expt Therapeut, Div Clin Pharmacol, Rochester, MN USATongzheng Liu - Mayo ClinicJunmei Cairns - Mayo Clin, Coll Med, Dept Mol Pharmacol & Expt Therapeut, Div Clin Pharmacol, Rochester, MN USAReynold C. Ly - Mayo Clin, Coll Med, Dept Mol Pharmacol & Expt Therapeut, Div Clin Pharmacol, Rochester, MN USAXianglin Tan - Rutgers Cancer InstituteMin Deng - Mayo ClinicBrooke L. Fridley - University of Kansas Medical CenterKrishna R. Kalari - Mayo ClinicRyan P. Abo - Massachusetts Institute of TechnologyGregory Jenkins - Mayo ClinicAnthony Batzler - Mayo ClinicErin E. Carlson - Mayo ClinicPoulami Barman - Mayo ClinicSebastian Moran - Institut d'Investigació Biomédica de BellvitgeHolger Heyn - Institut d'Investigació Biomédica de BellvitgeManel Esteller - Institut d'Investigació Biomédica de BellvitgeLiewei Wang - Mayo Clin, Coll Med, Dept Mol Pharmacol & Expt Therapeut, Div Clin Pharmacol, Rochester, MN USA
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.25(21), pp.4819-4834
- DOI
- 10.1093/hmg/ddw301
- PMID
- 28173075
- PMCID
- PMC6078562
- NLM abbreviation
- Hum Mol Genet
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Publisher
- Oxford Univ Press
- Number of pages
- 16
- Grant note
- ICREA R01CA084354 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) U19GM061388 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) R01CA196648; R01 CA138461; U19 GM61388; R01 CA80127; R01 CA84354; R01 CA105857 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 11/01/2016
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984701643502771
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