The histone demethylase JMJD2B plays an essential role in human carcinogenesis through positive regulation of cyclin-dependent kinase 6.

Abstract

Histone methyltransferases and demethylases are known to regulate transcription by altering the epigenetic marks on histones, but the pathologic roles of their dysfunction in human diseases, such as cancer, still remain to be elucidated. Herein, we show that the histone demethylase JMJD2B is involved in human carcinogenesis. Quantitative real-time PCR showed notably elevated levels of JMJD2B expression in bladder cancers, compared with corresponding nonneoplastic tissues (P < 0.0001), and elevated protein expression was confirmed by immunohistochemistry. In addition, cDNA microarray analysis revealed transactivation of JMJD2B in lung cancer, and immunohistochemical analysis showed protein overexpression in lung cancer. siRNA-mediated reduction of expression of JMJD2B in bladder and lung cancer cell lines significantly suppressed the proliferation of cancer cells, and suppressing JMJD2B expression lead to a decreased population of cancer cells in S phase, with a concomitant increase of cells in G(1) phase. Furthermore, a clonogenicity assay showed that the demethylase activity of JMJD2B possesses an oncogenic activity. Microarray analysis after knockdown of JMJD2B revealed that JMJD2B could regulate multiple pathways which contribute to carcinogenesis, including the cell-cycle pathway. Of the downstream genes, chromatin immunoprecipitation showed that CDK6 (cyclin-dependent kinase 6), essential in G(1)-S transition, was directly regulated by JMJD2B, via demethylation of histone H3-K9 in its promoter region. Expression levels of JMJD2B and CDK6 were significantly correlated in various types of cell lines. Deregulation of histone demethylation resulting in perturbation of the cell cycle, represents a novel mechanism for human carcinogenesis and JMJD2B is a feasible molecular target for anticancer therapy.

• Authors: Gouji Toyokawa, Hyun-Soo Cho, Yukiko Iwai, Masanori Yoshimatsu, Masashi Takawa, Shinya Hayami, Kazuhiro Maejima, Noriaki Shimizu, Hirotoshi Tanaka, Tatsuhiko Tsunoda, Helen I Field, John D Kelly, David E Neal, Bruce A J Ponder, Yoshihiko Maehara, Yusuke Nakamura, Ryuji Hamamoto
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 4 Issue 12 Pg. 2051-61 (Dec 2011) ISSN: 1940-6215 [Electronic] United States
• PMID: 21930796 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2011 AACR

Chemical References

• Biomarkers, Tumor
• RNA, Messenger
• RNA, Small Interfering
• Jumonji Domain-Containing Histone Demethylases
• KDM4B protein, human
• CDK6 protein, human
• Cyclin-Dependent Kinase 6

Topics

• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Blotting, Western
• Cell Cycle
• Cell Line, Tumor
• Cell Proliferation
• Chromatin Immunoprecipitation
• Cyclin-Dependent Kinase 6 (genetics, metabolism)
• DNA Methylation
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Immunoenzyme Techniques
• Jumonji Domain-Containing Histone Demethylases (antagonists & inhibitors, genetics, metabolism)
• Lung Neoplasms (genetics, metabolism, pathology)
• Oligonucleotide Array Sequence Analysis
• RNA, Messenger (genetics)
• RNA, Small Interfering (genetics)
• Real-Time Polymerase Chain Reaction
• Urinary Bladder (metabolism)
• Urinary Bladder Neoplasms (genetics, metabolism, pathology)