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

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 ga...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2019-01, Vol.79 (1), p.196-208
Hauptverfasser: Polusani, Srikanth R, Huang, Yi-Wen, Huang, Guangcun, Chen, Chun-Wei, Wang, Chiou-Miin, Lin, Li-Ling, Osmulski, Pawel, Lucio, Nicholas D, Liu, Lu, Hsu, Ya-Ting, Zhou, Yufan, Lin, Chun-Lin, Aguilera-Barrantes, Irene, Valente, Philip T, Kost, Edward R, Chen, Chun-Liang, Shim, Eun Yong, Lee, Sang Eun, Ruan, Jianhua, Gaczynska, Maria E, Yan, Pearlly, Goodfellow, Paul J, Mutch, David G, Jin, Victor X, Nicholson, Bruce J, Huang, Tim H-M, Kirma, Nameer B
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Sprache:eng
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Zusammenfassung: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 coculture system revealed transcriptional repression of (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 repression profile, suggesting that PAI-1 may mediate actions of ASC on transcriptional regulation in EEC. In an endometrial cancer cohort ( = 141), DNA hypermethylation of and related loci and 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 . 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 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.
ISSN:0008-5472
1538-7445
1538-7445
DOI:10.1158/0008-5472.CAN-18-1615