The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15 ^Ink4b

Abstract

The Ink4a/Arf/Ink4b locus plays a critical role in both cellular senescence and tumorigenesis. Jhdm1b/Kdm2b/Fbxl10, the mammalian paralogue of the histone demethylase Jhdm1a/Kdm2a/Fbxl11, has been implicated in cell cycle regulation and tumorigenesis. In this report, we demonstrate that Jhdm1b is an H3K36 demethylase. Knockdown of Jhdm1b in primary MEFs inhibits cell proliferation and induces cellular senescence in a pRb and p53 pathway-dependent manner. Importantly, the effect of Jhdm1b on cell proliferation and cellular senescence is mediated through de-repression of p15 ^Ink4b as loss of p15 ^Ink4b function rescues cell proliferation defects in Jhdm1b knockdown cells. Chromatin immunoprecipitation on ectopically expressed Jhdm1b demonstrates that Jhdm1b targets the p15 ^Ink4b 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 p15 ^Ink4b.