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 Yong Shim; Sang Eun Lee; Jianhua Ruan; Maria E. Gaczynska; Pearlly Yan; Paul J. Goodfellow; David G. Mutch; Victor X. Jin; Bruce J. Nicholson; Tim H.M. Huang; Nameer B. Kirma

doi:10.1158/0008-5472.CAN-18-1615

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 Yong Shim, Sang Eun Lee, Jianhua Ruan, Maria E. GaczynskaPearlly Yan, Paul J. Goodfellow, David G. Mutch, Victor X. Jin, Bruce J. Nicholson, Tim H.M. Huang, Nameer B. Kirma

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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.

Original language	English
Pages (from-to)	196-208
Number of pages	13
Journal	Cancer research
Volume	79
Issue number	1
DOIs	https://doi.org/10.1158/0008-5472.CAN-18-1615
State	Published - Jan 1 2019

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10.1158/0008-5472.CAN-18-1615

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Polusani, S. R., Huang, Y. W., Huang, G., Chen, C. W., Wang, C. M., Lin, L. L., Osmulski, P., Lucio, N. D., Liu, L., Hsu, Y. T., Zhou, Y., Lin, C. L., Aguilera-Barrantes, I., Valente, P. T., Kost, E. R., Chen, C. L., Shim, E. Y., Lee, S. E., Ruan, J., ... 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

@article{a7439c9306fe405c89251897702705f1,

title = "Adipokines deregulate cellular communication via epigenetic repression of gap junction loci in obese endometrial cancer",

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.",

author = "Polusani, {Srikanth R.} and Huang, {Yi Wen} and Guangcun Huang and Chen, {Chun Wei} and Wang, {Chiou Miin} and Lin, {Li Ling} and Pawel Osmulski and Lucio, {Nicholas D.} and Lu Liu and Hsu, {Ya Ting} and Yufan Zhou and Lin, {Chun Lin} and Irene Aguilera-Barrantes and Valente, {Philip T.} and Kost, {Edward R.} and Chen, {Chun Liang} and Shim, {Eun Yong} and Lee, {Sang Eun} and Jianhua Ruan and Gaczynska, {Maria E.} and Pearlly Yan and Goodfellow, {Paul J.} and Mutch, {David G.} and Jin, {Victor X.} and Nicholson, {Bruce J.} and Huang, {Tim H.M.} and Kirma, {Nameer B.}",

note = "Publisher Copyright: {\textcopyright} 2019 American Association for Cancer Research.",

year = "2019",

month = jan,

day = "1",

doi = "10.1158/0008-5472.CAN-18-1615",

language = "English",

volume = "79",

pages = "196--208",

journal = "Cancer research",

issn = "0008-5472",

number = "1",

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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, CL, Shim, EY, Lee, SE, Ruan, J, Gaczynska, ME, Yan, P, Goodfellow, PJ, Mutch, DG, Jin, VX, Nicholson, BJ, Huang, THM & 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

TY - JOUR

T1 - Adipokines deregulate cellular communication via epigenetic repression of gap junction loci in obese endometrial cancer

AU - Polusani, Srikanth R.

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 Yong

AU - Lee, Sang Eun

AU - Ruan, Jianhua

AU - Gaczynska, Maria E.

AU - Yan, Pearlly

AU - Goodfellow, Paul J.

AU - Mutch, David G.

AU - Jin, Victor X.

AU - Nicholson, Bruce J.

AU - Huang, Tim H.M.

AU - Kirma, Nameer B.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85059446400&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-18-1615

DO - 10.1158/0008-5472.CAN-18-1615

M3 - Article

C2 - 30389702

AN - SCOPUS:85059446400

SN - 0008-5472

VL - 79

SP - 196

EP - 208

JO - Cancer research

JF - Cancer research

IS - 1

ER -

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

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