TET1 inhibits cell proliferation by inducing RASSF5 expression.
TET1 inhibits cell proliferation by inducing RASSF5 expression.
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TET1 通过诱导 RASSF5 表达来抑制细胞增殖。
DOI：
10.18632/oncotarget.21189
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发表时间：
2017-10-17
期刊：
影响因子：
--
通讯作者：
Pan WW
中科院分区：
文献类型：
--
作者：
Li BT;Yu C;Xu Y;Liu SB;Fan HY;Pan WW
泰特甲基胞嘧啶双加氧酶（Tet）催化5-甲基胞嘧啶氧化为5-羟甲基胞嘧啶（5hmC）。然而，TET1在卵巢癌细胞生长中的作用尚不清楚。在这里，我们发现TET1的异位表达增加了卵巢癌细胞系中5hmC的水平，并抑制了增殖和集落形成。此外，体外和体内功能研究表明，TET1过表达是抑制卵巢癌生长所必需的，而TET1表达的缺失具有相反的效果。此外，RNA-seq和qRT-PCR分析的结果确定了肿瘤抑制因子Ras相关结构域家族成员5（RASSF5）作为TET1的关键下游靶标。TET1通过使RASSF5启动子内的CpG位点去甲基化来促进RASSF5表达。RASSF5表达上调导致卵巢癌细胞生长抑制。此外，我们证明了CUL4-DDB1泛素连接酶复合物的抑制降低了卵巢癌细胞中的5hmC水平。这些结果为了解卵巢癌如何发展和生长提供了新的见解，并将TET1确定为这一过程中的关键参与者。
Tet methylcytosine dioxygenases (TETs) catalyze the oxidative reactions of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). However, TET1 roles in ovarian cancer cell growth are unknown. Here, we show that ectopic expression of TET1 increased 5hmC levels, and inhibited proliferation and colony formation in ovarian cancer cell lines. Furthermore, in vitro and in vivo functional studies demonstrated that TET1 overexpression is necessary for the suppression of ovarian cancer growth, whereas depletion of TET1 expression had the opposite effect. Furthermore, the results of RNA-seq and qRT-PCR analyses identified a tumor suppressor, Ras association domain family member 5 (RASSF5), as the key downstream target of TET1. TET1 promotes RASSF5 expression by demethylating a CpG site within RASSF5 promoter. Up-regulated RASSF5 expression leads to the suppression of ovarian cancer cells growth. Additionally, we demonstrated that inhibition of CUL4-DDB1 ubiquitin ligase complex decrease 5hmC levels in ovarian cancer cells. These results provide new insights into the understanding of how ovarian cancers develop and grow, and identify TET1 as a key player in this process.