Adipokines deregulate cellular communication via epigenetic repression of gap junction loci in obese endometrial cancer

Srikanth R. Polusani, Yi Wen Huang, Guangcun Huang, Chun Wei Chen, Chiou Miin Wang, Li Ling Lin, Pawel Osmulski, Nicholas D. Lucio, Lu Liu, Ya Ting Hsu, Yufan Zhou, Chun Lin Lin, Irene Aguilera-Barrantes, Philip T Valente, Edward R Kost, Chun-liang Chen, Eun Shim, Sang Lee, Jianhua Ruan, Maria E Gaczynska & 7 others Pearlly Yan, Paul J. Goodfellow, David G. Mutch, Victor X Jin, Bruce J Nicholson, Hui-ming Huang, Nameer B Kirma

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 transcrip-tome 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 ¼ 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.

Original languageEnglish (US)
Pages (from-to)196-208
Number of pages13
JournalCancer Research
Volume79
Issue number1
DOIs
StatePublished - Jan 1 2019

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Epigenetic Repression
Adipokines
Gap Junctions
Endometrial Neoplasms
Communication
Stromal Cells
Connexin 43
Obesity
Epithelial Cells
Plasminogen Activator Inhibitor 1
Neoplasms
Connexins
DNA Methylation
Endometrium
Coculture Techniques
Adipocytes
Genes
Cell Movement
Stem Cells
DNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Polusani, S. R., Huang, Y. W., Huang, G., Chen, C. W., Wang, C. M., Lin, L. L., ... Kirma, N. B. (2019). Adipokines deregulate cellular communication via epigenetic repression of gap junction loci in obese endometrial cancer. Cancer Research, 79(1), 196-208. https://doi.org/10.1158/0008-5472.CAN-18-1615

Adipokines deregulate cellular communication via epigenetic repression of gap junction loci in obese endometrial cancer. / 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; Lee, Sang; Ruan, Jianhua; Gaczynska, Maria E; Yan, Pearlly; Goodfellow, Paul J.; Mutch, David G.; Jin, Victor X; Nicholson, Bruce J; Huang, Hui-ming; Kirma, Nameer B.

In: Cancer Research, Vol. 79, No. 1, 01.01.2019, p. 196-208.

Research output: Contribution to journalArticle

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, C, Shim, E, Lee, S, Ruan, J, Gaczynska, ME, Yan, P, Goodfellow, PJ, Mutch, DG, Jin, VX, Nicholson, BJ, Huang, H & Kirma, NB 2019, 'Adipokines deregulate cellular communication via epigenetic repression of gap junction loci in obese endometrial cancer', Cancer Research, vol. 79, no. 1, pp. 196-208. https://doi.org/10.1158/0008-5472.CAN-18-1615
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 ; Lee, Sang ; Ruan, Jianhua ; Gaczynska, Maria E ; Yan, Pearlly ; Goodfellow, Paul J. ; Mutch, David G. ; Jin, Victor X ; Nicholson, Bruce J ; Huang, Hui-ming ; Kirma, Nameer B. / Adipokines deregulate cellular communication via epigenetic repression of gap junction loci in obese endometrial cancer. In: Cancer Research. 2019 ; Vol. 79, No. 1. pp. 196-208.
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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 transcrip-tome 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 ¼ 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.",
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AU - Huang, Yi Wen

AU - Huang, Guangcun

AU - Chen, Chun Wei

AU - Wang, Chiou Miin

AU - Lin, Li Ling

AU - Osmulski, Pawel

AU - Lucio, Nicholas D.

AU - Liu, Lu

AU - Hsu, Ya Ting

AU - Zhou, Yufan

AU - Lin, Chun Lin

AU - Aguilera-Barrantes, Irene

AU - Valente, Philip T

AU - Kost, Edward R

AU - Chen, Chun-liang

AU - Shim, Eun

AU - Lee, Sang

AU - Ruan, Jianhua

AU - Gaczynska, Maria E

AU - Yan, Pearlly

AU - Goodfellow, Paul J.

AU - Mutch, David G.

AU - Jin, Victor X

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AU - Huang, Hui-ming

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