Metformin pharmacogenomics: A genome-wide association study to identify genetic and epigenetic biomarkers involved in metformin anticancer response using human lymphoblastoid cell lines

Nifang Niu, Tongzheng Liu, Junmei Cairns, Reynold C. Ly, Xianglin Tan, Min Deng, Brooke L. Fridley, Krishna R Kalari, Ryan P. Abo, Gregory Jenkins, Anthony Batzler, Erin E. Carlson, Poulami Barman, Sebastian Moran, Holger Heyn, Manel Esteller, Liewei M Wang

Research output: Contribution to journalArticle

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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. Genomewide 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.

Original languageEnglish (US)
Pages (from-to)4819-4834
Number of pages16
JournalHuman Molecular Genetics
Volume25
Issue number21
DOIs
StatePublished - 2016

Fingerprint

Metformin
Genome-Wide Association Study
Pharmacogenetics
Epigenomics
Biomarkers
Cell Line
Single Nucleotide Polymorphism
DNA Methylation
Inhibitory Concentration 50
Genes
Breast Neoplasms
Cyclin A
Messenger RNA
Ubiquitin-Protein Ligases
DNA Probes
Proteasome Endopeptidase Complex
Antineoplastic Agents
Methylation
Small Interfering RNA
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Metformin pharmacogenomics : A genome-wide association study to identify genetic and epigenetic biomarkers involved in metformin anticancer response using human lymphoblastoid cell lines. / Niu, Nifang; Liu, Tongzheng; Cairns, Junmei; Ly, Reynold C.; Tan, Xianglin; Deng, Min; Fridley, Brooke L.; Kalari, Krishna R; Abo, Ryan P.; Jenkins, Gregory; Batzler, Anthony; Carlson, Erin E.; Barman, Poulami; Moran, Sebastian; Heyn, Holger; Esteller, Manel; Wang, Liewei M.

In: Human Molecular Genetics, Vol. 25, No. 21, 2016, p. 4819-4834.

Research output: Contribution to journalArticle

Niu, N, Liu, T, Cairns, J, Ly, RC, Tan, X, Deng, M, Fridley, BL, Kalari, KR, Abo, RP, Jenkins, G, Batzler, A, Carlson, EE, Barman, P, Moran, S, Heyn, H, Esteller, M & Wang, LM 2016, '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, no. 21, pp. 4819-4834. https://doi.org/10.1093/hmg/ddw301
Niu, Nifang ; Liu, Tongzheng ; Cairns, Junmei ; Ly, Reynold C. ; Tan, Xianglin ; Deng, Min ; Fridley, Brooke L. ; Kalari, Krishna R ; Abo, Ryan P. ; Jenkins, Gregory ; Batzler, Anthony ; Carlson, Erin E. ; Barman, Poulami ; Moran, Sebastian ; Heyn, Holger ; Esteller, Manel ; Wang, Liewei M. / Metformin pharmacogenomics : A genome-wide association study to identify genetic and epigenetic biomarkers involved in metformin anticancer response using human lymphoblastoid cell lines. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 21. pp. 4819-4834.
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