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

Howard Hughes Medical Institute, Chapel Hill, North Carolina 27599-7295, USA.
Nature Structural & Molecular Biology (Impact Factor: 13.31). 10/2008; 15(11):1169-1175. DOI: 10.1038/nsmb.1499


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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Available from: Yuichi Tsukada, May 28, 2015
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    • "Major components include altered methylation status of double stranded DNA and histones. The histone(lysine) demethylase KDM2B, the first identified human paralog of the Jumanji C (JmjC)-domain-containing histone demethylase 1b (Jhdm1b), has been implicated in cell-cycle regulation and tumorogenesis [4]. KDM2B represses Ink4/Arf via EZH2, the catalytic subunit of the polycomb repressive complex 2, a highly conserved histone methyltransferase that targets lysine-27 of histone H3, and interferes with cell proliferation and cellular senescence [5]. "
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    • "In addition, hKDM2B is required for Hox9a/Meis1- induced leukemic transformation, and hKDM2B regulates leukemic cell proliferation by directly repressing the expression of the tumor suppressor Ink4b (He et al., 2011). Similarly, depletion of KDM2B in primary mouse embryonic fibroblasts inhibits cell proliferation and induces senescence by direct depression of the Ink4b locus (He et al., 2008). Moreover, it was reported that KDM2B inhibits replicative or Ras-induced senescence by directly repressing the Ink4a/Arf locus in cultured mouse embryonic fibroblasts (Pfau et al., 2008; Tzatsos et al., 2009). "
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