Abstract
Histone methylation is an important epigenetic phenomenon that participates in a diverse array of cellular processes and has been found to be associated with cancer. Recent identification of several histone demethylases has proved that histone methylation is a reversible process. Through a candidate approach, we have biochemically identified JMJD3 as an H3K27 demethylase. Transfection of JMJD3 into HeLa cells caused a specific reduction of trimethyl H3K27, but had no effect on di- and monomethyl H3K27, or histone lysine methylations on H3K4 and H3K9. The enzymatic activity requires the JmjC domain and the conserved histidine that has been suggested to be important for a cofactor binding. In vitro biochemical experiments demonstrated that JMJD3 directly catalyzes the demethylation. In addition, we found that JMJD3 is upregulated in prostate cancer, and its expression is higher in metastatic prostate cancer. Thus, we identified JMJD3 as a demethylase capable of removing the trimethyl group from histone H3 lysine 27 and upregulated in prostate cancer.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Strahl BD, Allis CD . The language of covalent histone modifications. Nature 2000; 403:41–45.
Bannister AJ, Kouzarides T . Reversing histone methylation. Nature 2005; 436:1103–1106.
Bedford MT, Richard S . Arginine methylation an emerging regulator of protein function. Mol Cell 2005; 18:263–272.
Volpe TA, Kidner C, Hall IM, et al. Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science 2002; 297:1833–1837.
Plath K, Fang J, Mlynarczyk-Evans SK, et al. Role of histone H3 lysine 27 methylation in X inactivation. Science 2003; 300:131–135.
Cloos PA, Christensen J, Agger K, et al. The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 2006; 442:307–311.
Klose RJ, Yamane K, Bae Y, et al. The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36. Nature 2006; 442:312–316.
Shi Y, Lan F, Matson C, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 2004; 119:941–953.
Tsukada Y, Fang J, Erdjument-Bromage H, et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 2006; 439:811–816.
Whetstine JR, Nottke A, Lan F, et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 2006; 125:467–481.
Yamane K, Toumazou C, Tsukada Y, et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell 2006; 125:483–495.
Christensen J, Agger K, Cloos PA, et al. RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell 2007; 128:1063–1076.
Klose RJ, Yan Q, Tothova Z, et al. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell 2007; 128:889–900.
Lee MG, Norman J, Shilatifard A, Shiekhattar R . Physical and functional association of a trimethyl H3K4 demethylase and Ring6a/MBLR, a polycomb-like protein. Cell 2007; 128:877–887.
Yamane K, Tateishi K, Klose RJ, et al. PLU-1 is an H3K4 demethylase involved in transcriptional repression and breast cancer cell proliferation. Mol Cell 2007; 25:801–812.
Iwase S, Lan F, Bayliss P, et al. The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell 2007; 128:1077–1088.
Metzger E, Wissmann M, Yin N, et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 2005; 437:436–439.
Shi YJ, Matson C, Lan F, et al. Regulation of LSD1 histone demethylase activity by its associated factors. Mol Cell 2005; 19:857–864.
Li X, Tsuji I, Kuwahara M, et al. Mass screening of prostate cancer in Changchun City of China. Int Urol Nephrol 2004; 36:541–548.
Seligson DB, Horvath S, Shi T, et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 2005; 435:1262–1266.
Varambally S, Dhanasekaran SM, Zhou M, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 2002; 419:624–629.
Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004; 10:33–39.
Klose RJ, Kallin EM, Zhang Y . JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet 2006; 7:715–727.
Xiang Y, Chen C, et al. Unpublished data;
Chen Z, Zang J, Whetstine J, et al. Structural insights into histone demethylation by JMJD2 family members. Cell 2006; 125:691–702.
Rhodes DR, Yu J, Shanker K, et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 2004; 6:1–6.
Agger K, Cloos PA, Christensen J, et al. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 2007; doi:10.1038/nature06147.
Shi B, Liang J, Yang X, et al. Integration of estrogen and Wnt signaling circuits by the polycomb group protein EZH2 in breast cancer cells. Mol Cell Biol 2007; 27:5105–5119.
Reik W . Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 2007; 447:425–432.
Acknowledgements
We are grateful to Kazusa DNA Research Institute (Japan) for JMJD3 cDNA (KIAA0346) and to Dr Jenuwein (Research Institute of Molecular Pathology, Austria) for H3K27me3 antibody. This work was supported by Chinese Academy of Sciences (KSCX2-YW-R-04), National Basic Research Program of China (973 Program) (2007CB947900) and Shanghai Pujiang Plan (07pj14097).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Xiang, Y., Zhu, Z., Han, G. et al. JMJD3 is a histone H3K27 demethylase. Cell Res 17, 850–857 (2007). https://doi.org/10.1038/cr.2007.83
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/cr.2007.83
Keywords
This article is cited by
-
KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress
Leukemia (2023)
-
The H3K27 demethylase controls the lateral line embryogenesis of zebrafish
Cell Biology and Toxicology (2023)
-
Histone demethylase JMJD3 downregulation protects against aberrant force-induced osteoarthritis through epigenetic control of NR4A1
International Journal of Oral Science (2022)
-
JMJD family proteins in cancer and inflammation
Signal Transduction and Targeted Therapy (2022)
-
The heterogeneity of microglial activation and its epigenetic and non-coding RNA regulations in the immunopathogenesis of neurodegenerative diseases
Cellular and Molecular Life Sciences (2022)
