Epigenetic targeting of adipocytes inhibits high-grade serous ovarian cancer cell migration and invasion

Jessica Tang, Nicholas Pulliam, Ali Ozeş, Aaron Buechlein, Ning Ding, Harold Keer, Doug Rusch, Heather O'Hagan, M. Sharon Stack, Kenneth Nephew

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Ovarian cancer (OC) cells frequently metastasize to the omentum, and adipocytes play a significant role in ovarian tumor progression. Therapeutic interventions targeting aberrant DNA methylation in ovarian tumors have shown promise in the clinic, but the effects of epigenetic therapy on the tumor microenvironment are understudied. Here, we examined the effect of adipocytes on OC cell behavior in culture and impact of targeting DNA methylation in adipocytes on OC metastasis. The presence of adipocytes increased OC cell migration and invasion, and proximal and direct coculture of adipocytes increased OC proliferation alone or after treatment with carboplatin. Treatment of adipocytes with hypomethylating agent guadecitabine decreased migration and invasion of OC cells toward adipocytes. Subcellular protein fractionation of adipocytes treated with guadecitabine revealed decreased DNA methyltransferase 1 (DNMT1) levels even in the presence of DNA synthesis inhibitor, aphidicolin. Methyl-Capture- and RNA-sequencing analysis of guadecitabine-treated adipocytes revealed derepression of tumor-suppressor genes and epithelial–mesenchymal transition inhibitors. SUSD2, a secreted tumor suppressor downregulated by promoter CpG island methylation in adipocytes, was upregulated after guadecitabine treatment, and recombinant SUSD2 decreased OC cell migration and invasion. Integrated analysis of the methylomic and transcriptomic data identified pathways associated with inhibition of matrix metalloproteases and fatty acid a-oxidation, suggesting a possible mechanism of how epigenetic therapy of adipocytes decreases metastasis. In conclusion, the effect of DNMT inhibitor on fully differentiated adipocytes suggests that hypomethylating agents may affect the tumor microenvironment to decrease cancer cell metastasis. Implications: Epigenetic targeting of tumor microenvironment can affect metastatic behavior of ovarian cancer cells.

Original languageEnglish (US)
Pages (from-to)1226-1240
Number of pages15
JournalMolecular Cancer Research
Volume16
Issue number8
DOIs
StatePublished - Aug 1 2018

Fingerprint

Adipocytes
Epigenomics
Ovarian Neoplasms
Cell Movement
Tumor Microenvironment
DNA Methylation
Neoplasm Metastasis
Neoplasms
Aphidicolin
Nucleic Acid Synthesis Inhibitors
RNA Sequence Analysis
CpG Islands
Omentum
Carboplatin
Methyltransferases
Metalloproteases
Coculture Techniques
Tumor Suppressor Genes
Methylation
Fatty Acids

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Epigenetic targeting of adipocytes inhibits high-grade serous ovarian cancer cell migration and invasion. / Tang, Jessica; Pulliam, Nicholas; Ozeş, Ali; Buechlein, Aaron; Ding, Ning; Keer, Harold; Rusch, Doug; O'Hagan, Heather; Sharon Stack, M.; Nephew, Kenneth.

In: Molecular Cancer Research, Vol. 16, No. 8, 01.08.2018, p. 1226-1240.

Research output: Contribution to journalArticle

Tang, J, Pulliam, N, Ozeş, A, Buechlein, A, Ding, N, Keer, H, Rusch, D, O'Hagan, H, Sharon Stack, M & Nephew, K 2018, 'Epigenetic targeting of adipocytes inhibits high-grade serous ovarian cancer cell migration and invasion', Molecular Cancer Research, vol. 16, no. 8, pp. 1226-1240. https://doi.org/10.1158/1541-7786.MCR-17-0406
Tang, Jessica ; Pulliam, Nicholas ; Ozeş, Ali ; Buechlein, Aaron ; Ding, Ning ; Keer, Harold ; Rusch, Doug ; O'Hagan, Heather ; Sharon Stack, M. ; Nephew, Kenneth. / Epigenetic targeting of adipocytes inhibits high-grade serous ovarian cancer cell migration and invasion. In: Molecular Cancer Research. 2018 ; Vol. 16, No. 8. pp. 1226-1240.
@article{db999d1db42a4972882a13907e092e10,
title = "Epigenetic targeting of adipocytes inhibits high-grade serous ovarian cancer cell migration and invasion",
abstract = "Ovarian cancer (OC) cells frequently metastasize to the omentum, and adipocytes play a significant role in ovarian tumor progression. Therapeutic interventions targeting aberrant DNA methylation in ovarian tumors have shown promise in the clinic, but the effects of epigenetic therapy on the tumor microenvironment are understudied. Here, we examined the effect of adipocytes on OC cell behavior in culture and impact of targeting DNA methylation in adipocytes on OC metastasis. The presence of adipocytes increased OC cell migration and invasion, and proximal and direct coculture of adipocytes increased OC proliferation alone or after treatment with carboplatin. Treatment of adipocytes with hypomethylating agent guadecitabine decreased migration and invasion of OC cells toward adipocytes. Subcellular protein fractionation of adipocytes treated with guadecitabine revealed decreased DNA methyltransferase 1 (DNMT1) levels even in the presence of DNA synthesis inhibitor, aphidicolin. Methyl-Capture- and RNA-sequencing analysis of guadecitabine-treated adipocytes revealed derepression of tumor-suppressor genes and epithelial–mesenchymal transition inhibitors. SUSD2, a secreted tumor suppressor downregulated by promoter CpG island methylation in adipocytes, was upregulated after guadecitabine treatment, and recombinant SUSD2 decreased OC cell migration and invasion. Integrated analysis of the methylomic and transcriptomic data identified pathways associated with inhibition of matrix metalloproteases and fatty acid a-oxidation, suggesting a possible mechanism of how epigenetic therapy of adipocytes decreases metastasis. In conclusion, the effect of DNMT inhibitor on fully differentiated adipocytes suggests that hypomethylating agents may affect the tumor microenvironment to decrease cancer cell metastasis. Implications: Epigenetic targeting of tumor microenvironment can affect metastatic behavior of ovarian cancer cells.",
author = "Jessica Tang and Nicholas Pulliam and Ali Ozeş and Aaron Buechlein and Ning Ding and Harold Keer and Doug Rusch and Heather O'Hagan and {Sharon Stack}, M. and Kenneth Nephew",
year = "2018",
month = "8",
day = "1",
doi = "10.1158/1541-7786.MCR-17-0406",
language = "English (US)",
volume = "16",
pages = "1226--1240",
journal = "Molecular Cancer Research",
issn = "1541-7786",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - Epigenetic targeting of adipocytes inhibits high-grade serous ovarian cancer cell migration and invasion

AU - Tang, Jessica

AU - Pulliam, Nicholas

AU - Ozeş, Ali

AU - Buechlein, Aaron

AU - Ding, Ning

AU - Keer, Harold

AU - Rusch, Doug

AU - O'Hagan, Heather

AU - Sharon Stack, M.

AU - Nephew, Kenneth

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Ovarian cancer (OC) cells frequently metastasize to the omentum, and adipocytes play a significant role in ovarian tumor progression. Therapeutic interventions targeting aberrant DNA methylation in ovarian tumors have shown promise in the clinic, but the effects of epigenetic therapy on the tumor microenvironment are understudied. Here, we examined the effect of adipocytes on OC cell behavior in culture and impact of targeting DNA methylation in adipocytes on OC metastasis. The presence of adipocytes increased OC cell migration and invasion, and proximal and direct coculture of adipocytes increased OC proliferation alone or after treatment with carboplatin. Treatment of adipocytes with hypomethylating agent guadecitabine decreased migration and invasion of OC cells toward adipocytes. Subcellular protein fractionation of adipocytes treated with guadecitabine revealed decreased DNA methyltransferase 1 (DNMT1) levels even in the presence of DNA synthesis inhibitor, aphidicolin. Methyl-Capture- and RNA-sequencing analysis of guadecitabine-treated adipocytes revealed derepression of tumor-suppressor genes and epithelial–mesenchymal transition inhibitors. SUSD2, a secreted tumor suppressor downregulated by promoter CpG island methylation in adipocytes, was upregulated after guadecitabine treatment, and recombinant SUSD2 decreased OC cell migration and invasion. Integrated analysis of the methylomic and transcriptomic data identified pathways associated with inhibition of matrix metalloproteases and fatty acid a-oxidation, suggesting a possible mechanism of how epigenetic therapy of adipocytes decreases metastasis. In conclusion, the effect of DNMT inhibitor on fully differentiated adipocytes suggests that hypomethylating agents may affect the tumor microenvironment to decrease cancer cell metastasis. Implications: Epigenetic targeting of tumor microenvironment can affect metastatic behavior of ovarian cancer cells.

AB - Ovarian cancer (OC) cells frequently metastasize to the omentum, and adipocytes play a significant role in ovarian tumor progression. Therapeutic interventions targeting aberrant DNA methylation in ovarian tumors have shown promise in the clinic, but the effects of epigenetic therapy on the tumor microenvironment are understudied. Here, we examined the effect of adipocytes on OC cell behavior in culture and impact of targeting DNA methylation in adipocytes on OC metastasis. The presence of adipocytes increased OC cell migration and invasion, and proximal and direct coculture of adipocytes increased OC proliferation alone or after treatment with carboplatin. Treatment of adipocytes with hypomethylating agent guadecitabine decreased migration and invasion of OC cells toward adipocytes. Subcellular protein fractionation of adipocytes treated with guadecitabine revealed decreased DNA methyltransferase 1 (DNMT1) levels even in the presence of DNA synthesis inhibitor, aphidicolin. Methyl-Capture- and RNA-sequencing analysis of guadecitabine-treated adipocytes revealed derepression of tumor-suppressor genes and epithelial–mesenchymal transition inhibitors. SUSD2, a secreted tumor suppressor downregulated by promoter CpG island methylation in adipocytes, was upregulated after guadecitabine treatment, and recombinant SUSD2 decreased OC cell migration and invasion. Integrated analysis of the methylomic and transcriptomic data identified pathways associated with inhibition of matrix metalloproteases and fatty acid a-oxidation, suggesting a possible mechanism of how epigenetic therapy of adipocytes decreases metastasis. In conclusion, the effect of DNMT inhibitor on fully differentiated adipocytes suggests that hypomethylating agents may affect the tumor microenvironment to decrease cancer cell metastasis. Implications: Epigenetic targeting of tumor microenvironment can affect metastatic behavior of ovarian cancer cells.

UR - http://www.scopus.com/inward/record.url?scp=85050958584&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85050958584&partnerID=8YFLogxK

U2 - 10.1158/1541-7786.MCR-17-0406

DO - 10.1158/1541-7786.MCR-17-0406

M3 - Article

C2 - 29759990

AN - SCOPUS:85050958584

VL - 16

SP - 1226

EP - 1240

JO - Molecular Cancer Research

JF - Molecular Cancer Research

SN - 1541-7786

IS - 8

ER -