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 language | English |
|---|---|
| Pages (from-to) | 2051-2061 |
| Number of pages | 11 |
| Journal | Cancer Prevention Research |
| Volume | 4 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Dec 1 2011 |
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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 journal › Article
}
TY - JOUR
T1 - The histone demethylase JMJD2B plays an essential role in human carcinogenesis through positive regulation of cyclin-dependent kinase 6
AU - Toyokawa, Gouji
AU - Cho, Hyun Soo
AU - Iwai, Yukiko
AU - Yoshimatsu, Masanori
AU - Takawa, Masashi
AU - Hayami, Shinya
AU - Maejima, Kazuhiro
AU - Shimizu, Noriaki
AU - Tanaka, Hirotoshi
AU - Tsunoda, Tatsuhiko
AU - Field, Helen I.
AU - Kelly, John D.
AU - Neal, David E.
AU - Ponder, Bruce A.J.
AU - Maehara, Yoshihiko
AU - Nakamura, Yusuke
AU - Hamamoto, Ryuji
PY - 2011/12/1
Y1 - 2011/12/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=83055162300&partnerID=8YFLogxK
U2 - 10.1158/1940-6207.CAPR-11-0290
DO - 10.1158/1940-6207.CAPR-11-0290
M3 - Article
C2 - 21930796
AN - SCOPUS:83055162300
VL - 4
SP - 2051
EP - 2061
JO - Cancer Prevention Research
JF - Cancer Prevention Research
SN - 1940-6207
IS - 12
ER -