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The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15Ink4b

Nature Structural & Molecular Biology volume 15, pages 1169–1175 (2008)Cite this article

Abstract

The Ink4a-Arf-Ink4b locus has a crucial role in both cellular senescence and tumorigenesis. JmjC domain–containing histone demethylase 1b (Jhdm1b, also known as Kdm2b and Fbxl10), the mammalian paralog of the histone demethylase Jhdm1a (also known as Kdm2a and Fbxl11), has been implicated in cell-cycle regulation and tumorigenesis. In this report, we show that Jhdm1b is a histone H3 lysine 36 (H3K36) demethylase. Knockdown of Jhdm1b in primary mouse embryonic fibroblasts inhibits cell proliferation and induces cellular senescence in a pRb- and p53 pathway–dependent manner. Notably, the effect of Jhdm1b on cell proliferation and cellular senescence is mediated through derepression of p15Ink4b, as loss of p15Ink4b function rescues cell-proliferation defects in Jhdm1b-knockdown cells. Chromatin immunoprecipitation on ectopically expressed Jhdm1b demonstrates that Jhdm1b targets the p15Ink4b locus and regulates its expression in an enzymatic activity–dependent manner. Alteration of Jhdm1b level affects Ras-induced neoplastic transformation. Collectively, our results indicate that Jhdm1b is an H3K36 demethylase that regulates cell proliferation and senescence through p15Ink4b.

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Figure 1: Jhdm1b is a H3K36-specific demethylase in vitro and in vivo.
Figure 2: Jhdm1b knockdown in primary MEFs inhibits cell proliferation and induces cellular senescence.
Figure 3: Jhdm1b regulates cell proliferation through p15Ink4b.
Figure 4: Jhdm1b regulates cell proliferation and p15Ink4b expression in a histone-demethylase activity–dependent manner.
Figure 5: Jhdm1b facilitates Ras-induced neoplastic transformation.

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Acknowledgements

We thank L. Wolff (US National Cancer Institute) for the p15Ink4b-null mice. This work is partially supported by the US National Institutes of Health (GM068804). J.H. is a fellow of the Leukemia and Lymphoma Society. Y.Z. is supported by the Howard Hughes Medical Institute.

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  1. Jin He and Eric M Kallin: These authors contributed equally to this work.

Authors and Affiliations

  1. Howard Hughes Medical Institute, Chapel Hill, 27599-7295, North Carolina, USA

    Jin He, Eric M Kallin, Yu-ichi Tsukada & Yi Zhang

  2. Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, 27599-7295, North Carolina, USA

    Jin He, Eric M Kallin, Yu-ichi Tsukada & Yi Zhang

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  1. Jin He
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Contributions

J.H. contributed data for Figures 2, 3, 4 and 5; E.M.K. contributed data for Figures 1 and 4; Y.T. constructed plasmids and generated the wild-type Jhdm1b baculovirus; Y.Z. oversaw the project; E.M.K., J.H., & Y.Z. wrote the paper.

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Correspondence to Yi Zhang.

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Supplementary Figures 1–5 and Supplementary Table 1 (PDF 1772 kb)

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He, J., Kallin, E., Tsukada, Yi. et al. The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15Ink4b. Nat Struct Mol Biol 15, 1169–1175 (2008). https://doi.org/10.1038/nsmb.1499

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