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Adipokines Deregulate Cellular Communication via Epigenetic Repression of Gap Junction Loci in Obese Endometrial Cancer.
- Source :
-
Cancer research [Cancer Res] 2019 Jan 01; Vol. 79 (1), pp. 196-208. Date of Electronic Publication: 2018 Nov 02. - Publication Year :
- 2019
-
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.<br /> (©2018 American Association for Cancer Research.)
- Subjects :
- Adipose Tissue metabolism
Animals
Cell Movement
Cells, Cultured
Connexin 43 metabolism
Diet, High-Fat adverse effects
Endometrial Neoplasms etiology
Endometrial Neoplasms metabolism
Epithelial Cells metabolism
Epithelial Cells pathology
Female
Gap Junctions
Humans
Mice
Mice, Knockout
Obesity physiopathology
Stromal Cells metabolism
Stromal Cells pathology
Adipokines pharmacology
Adipose Tissue pathology
Cell Communication
Connexin 43 genetics
Endometrial Neoplasms pathology
Epigenetic Repression
Obesity complications
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 79
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 30389702
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-18-1615