Format

Send to

Choose Destination
Cancer Res. 2019 Jan 1;79(1):196-208. doi: 10.1158/0008-5472.CAN-18-1615. Epub 2018 Nov 2.

Adipokines Deregulate Cellular Communication via Epigenetic Repression of Gap Junction Loci in Obese Endometrial Cancer.

Author information

1
Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, Texas.
2
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukie, Wisconsin.
3
Department of Computer Science, North Dakota State University, Fargo, North Dakota.
4
Department of Pathology, Medical College of Wisconsin, Milwaukie, Wisconsin.
5
Department of Pathology, University of Texas Health San Antonio, San Antonio, Texas.
6
Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
7
Department of Radiation Oncology, University of Texas Health San Antonio, San Antonio, Texas.
8
Department of Computer Science, University of Texas San Antonio, San Antonio, Texas.
9
Department of Internal Medicine, Ohio State University, Columbus, Ohio.
10
Department of Obstetrics and Gynecology, Ohio State University, Columbus, Ohio.
11
Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri.
12
Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, Texas.
13
Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, Texas. kirma@uthscsa.edu huangt3@uthscsa.edu.

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.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center