Faculty Collaboration Database

Adipokines Deregulate Cellular Communication via Epigenetic Repression of Gap Junction Loci in Obese Endometrial Cancer. Cancer Res 2019 Jan 01;79(1):196-208

Date

11/06/2018

Pubmed ID

30389702

Pubmed Central ID

PMC6705596

DOI

10.1158/0008-5472.CAN-18-1615

Scopus ID

2-s2.0-85059446400 (requires institutional sign-in at Scopus site)   17 Citations

Abstract

Emerging evidence indicates that adipose stromal cells (ASC) are recruited to enhance cancer development. In this study, we examined the role these adipocyte progenitors play relating to intercellular communication in obesity-associated endometrial cancer. This is particularly relevant given that gap junctions have been implicated in tumor suppression. Examining the effects of ASCs on the transcriptome of endometrial epithelial cells (EEC) in an in vitro coculture system revealed transcriptional repression of GJA1 (encoding the gap junction protein Cx43) and other genes related to intercellular communication. This repression was recapitulated in an obesity mouse model of endometrial cancer. Furthermore, inhibition of plasminogen activator inhibitor 1 (PAI-1), which was the most abundant ASC adipokine, led to reversal of cellular distribution associated with the GJA1 repression profile, suggesting that PAI-1 may mediate actions of ASC on transcriptional regulation in EEC. In an endometrial cancer cohort (n = 141), DNA hypermethylation of GJA1 and related loci TJP2 and PRKCA was observed in primary endometrial endometrioid tumors and was associated with obesity. Pharmacologic reversal of DNA methylation enhanced gap-junction intercellular communication and cell-cell interactions in vitro. Restoring Cx43 expression in endometrial cancer cells reduced cellular migration; conversely, depletion of Cx43 increased cell migration in immortalized normal EEC. Our data suggest that persistent repression by ASC adipokines leads to promoter hypermethylation of GJA1 and related genes in the endometrium, triggering long-term silencing of these loci in endometrial tumors of obese patients. SIGNIFICANCE: Studies reveal that adipose-derived stem cells in endometrial cancer pathogenesis influence epigenetic repression of gap junction loci, which suggests targeting of gap junction activity as a preventive strategy for obesity-associated endometrial cancer.

Author List

Polusani SR, Huang YW, Huang G, Chen CW, Wang CM, Lin LL, Osmulski P, Lucio ND, Liu L, Hsu YT, Zhou Y, Lin CL, Aguilera-Barrantes I, Valente PT, Kost ER, Chen CL, Shim EY, Lee SE, Ruan J, Gaczynska ME, Yan P, Goodfellow PJ, Mutch DG, Jin VX, Nicholson BJ, Huang TH, Kirma NB

Author

Victor X. Jin PhD Professor in the Data Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adipokines
Adipose Tissue
Animals
Cell Communication
Cell Movement
Cells, Cultured
Connexin 43
Diet, High-Fat
Endometrial Neoplasms
Epigenetic Repression
Epithelial Cells
Female
Gap Junctions
Humans
Mice
Mice, Knockout
Obesity
Stromal Cells