Demethylation of RB Regulator MYPT1 by Histone Demethylase LSD1 Promotes Cell Cycle Progression in Cancer Cells
Demethylation of RB Regulator MYPT1 by Histone Demethylase LSD1 Promotes Cell Cycle Progression in Cancer Cells
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DOI：
10.1158/0008-5472.can-10-2446
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发表时间：
2011-02-01
期刊：
影响因子：
11.2
通讯作者：
Hamamoto, Ryuji
中科院分区：
文献类型：
--
作者：
Cho, Hyun-Soo;Suzuki, Takehiro;Hamamoto, Ryuji
组蛋白去甲基化酶LSD 1（也称为KDM 1和AOF 2）在多种癌细胞中具有活性，但其在人类致癌中的生物学意义尚未探索。在这项研究中，我们探讨了LSD 1和MYPT 1（一种已知的RB 1磷酸化调节因子）之间的假设相互作用。我们发现MYPT 1在体外和体内被组蛋白赖氨酸甲基转移酶SETD 7甲基化，并被LSD 1去甲基化，确定MYPT 1的Lys 442为这些酶甲基化/去甲基化的靶点。LSD 1沉默增加MYPT 1蛋白水平，降低磷酸化RB 1（Ser 807/811）的稳态水平，并降低E2 F活性。MYPT 1甲基化状态影响MYPT 1对蛋白质周转的泛素-蛋白酶体途径的亲和力。MYPT 1在缺乏SETD 7的鼠细胞中不稳定，支持MYPT 1蛋白稳定性受甲基化状态生理调节的概念。LSD 1过表达可通过诱导MYPT 1蛋白的不稳定性来激活RB 1磷酸化。总之，我们的研究结果包括一个新的细胞周期调控机制介导的甲基化/去甲基化动力学，他们揭示了LSD 1过表达在人类肿瘤发生的意义。Cancer Res; 71（3）; 655-60.（C）2010年AACR。
Histone demethylase LSD1 (also known as KDM1 and AOF2) is active in various cancer cells, but its biological significance in human carcinogenesis is unexplored. In this study, we explored hypothesized interactions between LSD1 and MYPT1, a known regulator of RB1 phosphorylation. We found that MYPT1 was methylated in vitro and in vivo by histone lysine methyltransferase SETD7 and demethylated by LSD1, identifying Lys 442 of MYPT1 as a target for methylation/demethylation by these enzymes. LSD1 silencing increased MYPT1 protein levels, decreasing the steady state level of phosphorylated RB1 (Ser 807/811) and reducing E2F activity. MYPT1 methylation status influenced the affinity of MYPT1 for the ubiquitin-proteasome pathway of protein turnover. MYPT1 was unstable in murine cells deficient in SETD7, supporting the concept that MYPT1 protein stability is physiologically regulated by methylation status. LSD1 overexpression could activate RB1 phosphorylation by inducing a destabilization of MYPT1 protein. Taken together, our results comprise a novel cell cycle regulatory mechanism mediated by methylation/demethylation dynamics, and they reveal the significance of LSD1 overexpression in human carcinogenesis. Cancer Res; 71(3); 655-60. (C)2010 AACR.