Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
J Biol Chem. 2011 Sep 23;286(38):33061-9. doi: 10.1074/jbc.M111.257667. Epub 2011 Jul 11.
Sustained expression of the histone demethylase, KDM2B (Ndy1/FBXL10/JHDM1B), bypasses cellular senescence in primary mouse embryonic fibroblasts (MEFs). Here, we show that KDM2B is a conserved regulator of lifespan in multiple primary cell types and defines a program in which this chromatin-modifying enzyme counteracts the senescence-associated down-regulation of the EZH2 histone methyltransferase. Senescence in MEFs epigenetically silences KDM2B and induces the tumor suppressor miRNAs let-7b and miR-101, which target EZH2. Forced expression of KDM2B promotes immortalization by silencing these miRNAs through locus-specific histone H3 K36me2 demethylation, leading to EZH2 up-regulation. Overexpression of let-7b down-regulates EZH2, induces premature senescence, and counteracts immortalization of MEFs driven by KDM2B. The KDM2B-let-7-EZH2 pathway also contributes to the proliferation of immortal Ink4a/Arf null fibroblasts suggesting that, beyond its anti-senescence role in primary cells, this histone-modifying enzyme functions more broadly in the regulation of cellular proliferation.
组蛋白去甲基酶 KDM2B（Ndy1/FBXL10/JHDM1B）的持续表达可绕过原代小鼠胚胎成纤维细胞（MEF）中的细胞衰老。在这里，我们表明 KDM2B 是多种原代细胞类型中寿命的保守调节剂，并定义了一个程序，其中这种染色质修饰酶抵消了 EZH2 组蛋白甲基转移酶与衰老相关的下调。MEF 中的衰老通过表观遗传沉默 KDM2B 并诱导肿瘤抑制 miRNA let-7b 和 miR-101，从而靶向 EZH2。KDM2B 的强制表达通过特定位点的组蛋白 H3 K36me2 去甲基化沉默这些 miRNA 来促进永生化，导致 EZH2 上调。let-7b 的过表达下调 EZH2，诱导过早衰老，并抵消 KDM2B 驱动的 MEF 的永生化。KDM2B-let-7-EZH2 通路也有助于永生 Ink4a/Arf 缺失成纤维细胞的增殖，表明除了在原代细胞中的抗衰老作用外，这种组蛋白修饰酶在细胞增殖的调节中具有更广泛的功能。
