Histone Demethylase LSD2 Acts as an E3 Ubiquitin Ligase and Inhibits Cancer Cell Growth through Promoting Proteasomal Degradation of OGT
Histone Demethylase LSD2 Acts as an E3 Ubiquitin Ligase and Inhibits Cancer Cell Growth through Promoting Proteasomal Degradation of OGT
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组蛋白去甲基化酶 LSD2 作为 E3 泛素连接酶并通过促进 OGT 的蛋白酶体降解来抑制癌细胞生长
DOI：
10.1016/j.molcel.2015.01.038
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发表时间：
2015-04-02
期刊：
影响因子：
16
通讯作者：
Xu, Yanhui
中科院分区：
文献类型：
--
作者：
Yang, Yi;Yin, Xiaotong;Xu, Yanhui
组蛋白去甲基酶在各种生物过程中发挥着重要的作用，这种作用依赖于其去甲基酶的活性。然而，人们对它们的脱甲基酶非依赖性活性知之甚少。在这里，我们报道了LSD2，一个广为人知的组蛋白H3K4me1/me2去甲基酶，具有意想不到的E3泛素连接酶活性。LSD2直接泛素化和促进蛋白酶体依赖的O-GlcNAc转移酶(OGT)的降解，并以一种依赖于其E3连接酶活性而不是去甲基酶活性的方式抑制A549肺癌细胞的生长。LSD2的缺失稳定了OGT，促进了293T细胞的集落形成。LSD2分别通过组蛋白去甲基酶和E3连接酶的活性调节不同的靶基因群。这种调节表明，LSD2通过促进OGT和其他尚未发现的底物的降解来抑制肿瘤发生的机制。我们的研究揭示了LSD2的抗生长功能依赖于其E3连接酶的活性，并建立了组蛋白去甲基酶和泛素依赖途径之间的联系。
Histone demethylases play important roles in various biological processes in a manner dependent on their demethylase activities. However, little is known about their demethylase-independent activities. Here, we report that LSD2, a well-known histone H3K4me1/me2 demethylase, possesses an unexpected E3 ubiquitin ligase activity. LSD2 directly ubiquitylates and promotes proteasome-dependent degradation of O-GlcNAc transferase (OGT), and inhibits A549 lung cancer cell growth in a manner dependent on its E3 ligase activity, but not demethylase activity. The depletion of LSD2 stabilizes OGT and promotes colony formation of 293T cells. LSD2 regulates distinct groups of target genes through histone demethylase and E3 ligase activities, respectively. Such regulation suggests a mechanism through which LSD2 suppresses tumorigenesis by promoting the degradation of OGT and other substrates yet to be discovered. Our study reveals an antigrowth function of LSD2 dependent on its E3 ligase activity and establishes a connection between histone demethylase and ubiquitin-dependent pathway.