Histone Demethylase JMJD2B Functions as a Co-Factor of Estrogen Receptor in Breast Cancer Proliferation and Mammary Gland Development

• Published in: PloS one Vol. 6; no. 3; p. e17830
• Main Authors: Kawazu, Masahito, Saso, Kayoko, Tong, Kit I., McQuire, Tracy, Goto, Kouichiro, Son, Dong-Ok, Wakeham, Andrew, Miyagishi, Makoto, Mak, Tak W., Okada, Hitoshi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.03.2011; Public Library of Science (PLoS)
• Subjects: 17β-Estradiol; Animals; Antibiotics; Biology; Biophysics; Breast cancer; Breast Neoplasms - pathology; Breast Neoplasms - physiopathology; Cancer; Cancer treatment; Cell Line, Tumor; Cell Proliferation; Chromatin; Chromatin Immunoprecipitation; Chromatin remodeling; Clonal deletion; Development and progression; Epithelial cells; Estradiol; Estrogen Receptor alpha - physiology; Estrogen receptors; Estrogens; Ethics; Female; Females; Gene Targeting; Genes; Genomes; Genomics; Health care networks; Humans; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - physiology; Leukemia; Ligands; Lymphoma; Mammary gland; Mammary Glands, Animal - growth & development; Medical research; Medicine; Mice; Myc protein; Phenols (Class of compounds); Reproductive system; Reproductive systems; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA polymerase; Senescence; Sex hormones; Signal transduction; Signaling; Transcription; Transcription (Genetics); Transcription factors; Tumors; Xenograft Model Antitumor Assays; Toronto Ontario Canada; Canada; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0017830

Estrogen is a key regulator of normal function of female reproductive system and plays a pivotal role in the development and progression of breast cancer. Here, we demonstrate that JMJD2B (also known as KDM4B) constitutes a key component of the estrogen signaling pathway. JMJD2B is expressed in a high proportion of human breast tumors, and that expression levels significantly correlate with estrogen receptor (ER) positivity. In addition, 17-beta-estradiol (E2) induces JMJD2B expression in an ERα dependent manner. JMJD2B interacts with ERα and components of the SWI/SNF-B chromatin remodeling complex. JMJD2B is recruited to ERα target sites, demethylates H3K9me3 and facilitates transcription of ER responsive genes including MYB, MYC and CCND1. As a consequence, knockdown of JMJD2B severely impairs estrogen-induced cell proliferation and the tumor formation capacity of breast cancer cells. Furthermore, Jmjd2b-deletion in mammary epithelial cells exhibits delayed mammary gland development in female mice. Taken together, these findings suggest an essential role for JMJD2B in the estrogen signaling, and identify JMJD2B as a potential therapeutic target in breast cancer.