The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer

C. Wilson, L. Qiu, Y. Hong, T. Karnik, G. Tadros, B. Mau, T. Ma, Y. Mu, J. New, R. J. Louie, S. Gunewardena, A. K. Godwin, O. W. Tawfik, J. Chien, K. F. Roby, A. J. Krieg

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Epithelial ovarian cancer (EOC) has poor prognosis and rapid recurrence because of widespread dissemination of peritoneal metastases at diagnosis. Multiple pathways contribute to the aggressiveness of ovarian cancer, including hypoxic signaling mechanisms. In this study, we have determined that the hypoxia-inducible histone demethylase KDM4B is expressed in ∼60% of EOC tumors assayed, including primary and matched metastatic tumors. Expression of KDM4B in tumors is positively correlated with expression of the tumor hypoxia marker CA-IX, and is robustly induced in EOC cell lines exposed to hypoxia. KDM4B regulates expression of metastatic genes and pathways, and loss of KDM4B increases H3K9 trimethylation at the promoters of target genes like LOXL2, LCN2 and PDGFB. Suppressing KDM4B inhibits ovarian cancer cell invasion, migration and spheroid formation in vitro. KDM4B also regulates seeding and growth of peritoneal tumors in vivo, where its expression corresponds to hypoxic regions. This is the first demonstration that a Jumonji-domain histone demethylase regulates cellular processes required for peritoneal dissemination of cancer cells, one of the predominant factors affecting prognosis of EOC. The pathways regulated by KDM4B may present novel opportunities to develop combinatorial therapies to improve existing therapies for EOC patients.

Original languageEnglish (US)
Pages (from-to)2565-2576
Number of pages12
JournalOncogene
Volume36
Issue number18
DOIs
StatePublished - May 4 2017
Externally publishedYes

Fingerprint

Histone Demethylases
Ovarian Neoplasms
Neoplasms
Proto-Oncogene Proteins c-sis
Tumor Biomarkers
Cell Movement
Ovarian epithelial cancer
Neoplasm Metastasis
Gene Expression
Recurrence
Cell Line
Therapeutics
Growth
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Wilson, C., Qiu, L., Hong, Y., Karnik, T., Tadros, G., Mau, B., ... Krieg, A. J. (2017). The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer. Oncogene, 36(18), 2565-2576. https://doi.org/10.1038/onc.2016.412

The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer. / Wilson, C.; Qiu, L.; Hong, Y.; Karnik, T.; Tadros, G.; Mau, B.; Ma, T.; Mu, Y.; New, J.; Louie, R. J.; Gunewardena, S.; Godwin, A. K.; Tawfik, O. W.; Chien, J.; Roby, K. F.; Krieg, A. J.

In: Oncogene, Vol. 36, No. 18, 04.05.2017, p. 2565-2576.

Research output: Contribution to journalArticle

Wilson, C, Qiu, L, Hong, Y, Karnik, T, Tadros, G, Mau, B, Ma, T, Mu, Y, New, J, Louie, RJ, Gunewardena, S, Godwin, AK, Tawfik, OW, Chien, J, Roby, KF & Krieg, AJ 2017, 'The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer', Oncogene, vol. 36, no. 18, pp. 2565-2576. https://doi.org/10.1038/onc.2016.412
Wilson C, Qiu L, Hong Y, Karnik T, Tadros G, Mau B et al. The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer. Oncogene. 2017 May 4;36(18):2565-2576. https://doi.org/10.1038/onc.2016.412
Wilson, C. ; Qiu, L. ; Hong, Y. ; Karnik, T. ; Tadros, G. ; Mau, B. ; Ma, T. ; Mu, Y. ; New, J. ; Louie, R. J. ; Gunewardena, S. ; Godwin, A. K. ; Tawfik, O. W. ; Chien, J. ; Roby, K. F. ; Krieg, A. J. / The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer. In: Oncogene. 2017 ; Vol. 36, No. 18. pp. 2565-2576.
@article{72eb82711bca469783570554627b9bf3,
title = "The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer",
abstract = "Epithelial ovarian cancer (EOC) has poor prognosis and rapid recurrence because of widespread dissemination of peritoneal metastases at diagnosis. Multiple pathways contribute to the aggressiveness of ovarian cancer, including hypoxic signaling mechanisms. In this study, we have determined that the hypoxia-inducible histone demethylase KDM4B is expressed in ∼60{\%} of EOC tumors assayed, including primary and matched metastatic tumors. Expression of KDM4B in tumors is positively correlated with expression of the tumor hypoxia marker CA-IX, and is robustly induced in EOC cell lines exposed to hypoxia. KDM4B regulates expression of metastatic genes and pathways, and loss of KDM4B increases H3K9 trimethylation at the promoters of target genes like LOXL2, LCN2 and PDGFB. Suppressing KDM4B inhibits ovarian cancer cell invasion, migration and spheroid formation in vitro. KDM4B also regulates seeding and growth of peritoneal tumors in vivo, where its expression corresponds to hypoxic regions. This is the first demonstration that a Jumonji-domain histone demethylase regulates cellular processes required for peritoneal dissemination of cancer cells, one of the predominant factors affecting prognosis of EOC. The pathways regulated by KDM4B may present novel opportunities to develop combinatorial therapies to improve existing therapies for EOC patients.",
author = "C. Wilson and L. Qiu and Y. Hong and T. Karnik and G. Tadros and B. Mau and T. Ma and Y. Mu and J. New and Louie, {R. J.} and S. Gunewardena and Godwin, {A. K.} and Tawfik, {O. W.} and J. Chien and Roby, {K. F.} and Krieg, {A. J.}",
year = "2017",
month = "5",
day = "4",
doi = "10.1038/onc.2016.412",
language = "English (US)",
volume = "36",
pages = "2565--2576",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "18",

}

TY - JOUR

T1 - The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer

AU - Wilson, C.

AU - Qiu, L.

AU - Hong, Y.

AU - Karnik, T.

AU - Tadros, G.

AU - Mau, B.

AU - Ma, T.

AU - Mu, Y.

AU - New, J.

AU - Louie, R. J.

AU - Gunewardena, S.

AU - Godwin, A. K.

AU - Tawfik, O. W.

AU - Chien, J.

AU - Roby, K. F.

AU - Krieg, A. J.

PY - 2017/5/4

Y1 - 2017/5/4

N2 - Epithelial ovarian cancer (EOC) has poor prognosis and rapid recurrence because of widespread dissemination of peritoneal metastases at diagnosis. Multiple pathways contribute to the aggressiveness of ovarian cancer, including hypoxic signaling mechanisms. In this study, we have determined that the hypoxia-inducible histone demethylase KDM4B is expressed in ∼60% of EOC tumors assayed, including primary and matched metastatic tumors. Expression of KDM4B in tumors is positively correlated with expression of the tumor hypoxia marker CA-IX, and is robustly induced in EOC cell lines exposed to hypoxia. KDM4B regulates expression of metastatic genes and pathways, and loss of KDM4B increases H3K9 trimethylation at the promoters of target genes like LOXL2, LCN2 and PDGFB. Suppressing KDM4B inhibits ovarian cancer cell invasion, migration and spheroid formation in vitro. KDM4B also regulates seeding and growth of peritoneal tumors in vivo, where its expression corresponds to hypoxic regions. This is the first demonstration that a Jumonji-domain histone demethylase regulates cellular processes required for peritoneal dissemination of cancer cells, one of the predominant factors affecting prognosis of EOC. The pathways regulated by KDM4B may present novel opportunities to develop combinatorial therapies to improve existing therapies for EOC patients.

AB - Epithelial ovarian cancer (EOC) has poor prognosis and rapid recurrence because of widespread dissemination of peritoneal metastases at diagnosis. Multiple pathways contribute to the aggressiveness of ovarian cancer, including hypoxic signaling mechanisms. In this study, we have determined that the hypoxia-inducible histone demethylase KDM4B is expressed in ∼60% of EOC tumors assayed, including primary and matched metastatic tumors. Expression of KDM4B in tumors is positively correlated with expression of the tumor hypoxia marker CA-IX, and is robustly induced in EOC cell lines exposed to hypoxia. KDM4B regulates expression of metastatic genes and pathways, and loss of KDM4B increases H3K9 trimethylation at the promoters of target genes like LOXL2, LCN2 and PDGFB. Suppressing KDM4B inhibits ovarian cancer cell invasion, migration and spheroid formation in vitro. KDM4B also regulates seeding and growth of peritoneal tumors in vivo, where its expression corresponds to hypoxic regions. This is the first demonstration that a Jumonji-domain histone demethylase regulates cellular processes required for peritoneal dissemination of cancer cells, one of the predominant factors affecting prognosis of EOC. The pathways regulated by KDM4B may present novel opportunities to develop combinatorial therapies to improve existing therapies for EOC patients.

UR - http://www.scopus.com/inward/record.url?scp=84996636637&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84996636637&partnerID=8YFLogxK

U2 - 10.1038/onc.2016.412

DO - 10.1038/onc.2016.412

M3 - Article

C2 - 27869162

AN - SCOPUS:84996636637

VL - 36

SP - 2565

EP - 2576

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 18

ER -