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

作者：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^*

来源：Cancer Research, 2018.

DOI：10.1158/0008-5472.CAN-18-1615

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 co-culture 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.

• 单位
  Ohio state university; University of Texas Health Science Center at San Antonio; The Ohio State University; Medical college of Wisconsin; Washington University ,School of Medicine; North Dakota State University; The University of Texas at San Antonio; Washington University School of Medicine