KDM4B and KDM4A promote endometrial cancer progression by regulating androgen receptor, c-myc, and p27kip1

Oncotarget. 2015 Oct 13;6(31):31702-20. doi: 10.18632/oncotarget.5165.

Abstract

Epidemiological evidence suggests that elevated androgen levels and genetic variation related to the androgen receptor (AR) increase the risk of endometrial cancer (EC). However, the role of AR in EC is poorly understood. We report that two members of the histone demethylase KDM4 family act as major regulators of AR transcriptional activityin EC. In the MFE-296 cell line, KDM4B and AR upregulate c-myc expression, while in AN3CA cells KDM4A and AR downregulate p27kip1. Additionally, KDM4B expression is positively correlated with AR expression in EC cell lines with high baseline AR expression, while KDM4A and AR expression are positively correlated in low-AR cell lines. In clinical specimens, both KDM4B and KDM4A expression are significantly higher in EC tissues than that in normal endometrium. Finally, patients with alterations in AR, KDM4B, KDM4A, and c-myc have poor overall and disease-free survival rates. Together, these findings demonstrate that KDM4B and KDM4A promote EC progression by regulating AR activity.

Keywords: androgen receptor; c-myc; endometrial cancer; histone modification; lysine demethylases KDM4B and KDM4A; p27kip1; prognosis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Case-Control Studies
  • Cell Movement
  • Cell Proliferation
  • Chromatin Immunoprecipitation
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Disease Progression
  • Endometrial Neoplasms / genetics
  • Endometrial Neoplasms / metabolism
  • Endometrial Neoplasms / mortality
  • Endometrial Neoplasms / pathology*
  • Endometrium / metabolism
  • Endometrium / pathology
  • Female
  • Flow Cytometry
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunoenzyme Techniques
  • Immunoprecipitation
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Staging
  • Prognosis
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survival Rate
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • AR protein, human
  • CDKN1B protein, human
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • Receptors, Androgen
  • Cyclin-Dependent Kinase Inhibitor p27
  • Jumonji Domain-Containing Histone Demethylases
  • KDM4B protein, human
  • KDM4A protein, human