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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)2051-2061
Number of pages11
JournalCancer Prevention Research
Volume4
Issue number12
DOIs
Publication statusPublished - Dec 1 2011

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Cyclin-Dependent Kinase 6
Histone Demethylases
Lung Neoplasms
Carcinogenesis
Microarray Analysis
Urinary Bladder Neoplasms
Histones
Cell Cycle
Histone Code
Cell Line
Neoplasms
Gastrin-Secreting Cells
Chromatin Immunoprecipitation
Oligonucleotide Array Sequence Analysis
S Phase
Genetic Promoter Regions
Epigenomics
Small Interfering RNA
Transcriptional Activation
Real-Time Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

The histone demethylase JMJD2B plays an essential role in human carcinogenesis through positive regulation of cyclin-dependent kinase 6. / Toyokawa, Gouji; Cho, Hyun Soo; Iwai, Yukiko; Yoshimatsu, Masanori; Takawa, Masashi; Hayami, Shinya; Maejima, Kazuhiro; Shimizu, Noriaki; Tanaka, Hirotoshi; Tsunoda, Tatsuhiko; Field, Helen I.; Kelly, John D.; Neal, David E.; Ponder, Bruce A.J.; Maehara, Yoshihiko; Nakamura, Yusuke; Hamamoto, Ryuji.

In: Cancer Prevention Research, Vol. 4, No. 12, 01.12.2011, p. 2051-2061.

Research output: Contribution to journalArticle

Toyokawa, G, Cho, HS, Iwai, Y, Yoshimatsu, M, Takawa, M, Hayami, S, Maejima, K, Shimizu, N, Tanaka, H, Tsunoda, T, Field, HI, Kelly, JD, Neal, DE, Ponder, BAJ, Maehara, Y, Nakamura, Y & Hamamoto, R 2011, 'The histone demethylase JMJD2B plays an essential role in human carcinogenesis through positive regulation of cyclin-dependent kinase 6', Cancer Prevention Research, vol. 4, no. 12, pp. 2051-2061. https://doi.org/10.1158/1940-6207.CAPR-11-0290
Toyokawa, Gouji ; Cho, Hyun Soo ; Iwai, Yukiko ; Yoshimatsu, Masanori ; Takawa, Masashi ; Hayami, Shinya ; Maejima, Kazuhiro ; Shimizu, Noriaki ; Tanaka, Hirotoshi ; Tsunoda, Tatsuhiko ; Field, Helen I. ; Kelly, John D. ; Neal, David E. ; Ponder, Bruce A.J. ; Maehara, Yoshihiko ; Nakamura, Yusuke ; Hamamoto, Ryuji. / The histone demethylase JMJD2B plays an essential role in human carcinogenesis through positive regulation of cyclin-dependent kinase 6. In: Cancer Prevention Research. 2011 ; Vol. 4, No. 12. pp. 2051-2061.
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