LncRNA HOTAIR promotes human liver cancer stem cell malignant growth through downregulation of SETD2.
LncRNA HOTAIR promotes human liver cancer stem cell malignant growth through downregulation of SETD2.
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LncRNA HOTAIR通过下调SETD2促进人肝癌干细胞恶性生长
DOI：
10.18632/oncotarget.4443
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发表时间：
2015-09-29
期刊：
影响因子：
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通讯作者：
Lu D
中科院分区：
文献类型：
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作者：
Li H;An J;Wu M;Zheng Q;Gui X;Li T;Pu H;Lu D
长非编码RNA HOTAIR预测阴性肿瘤预后并显示致癌活性。在此，我们证明HOTAIR通过下调SETD 2促进人肝癌干细胞恶性生长。HOTAIR在机制上减少CREB、P300、RNA polII在抑制SETD 2表达及其磷酸化的SETD 2启动子区域上的再循环。因此，SETD 2与底物组蛋白H3的结合能力减弱，触发组蛋白H3第三十六赖氨酸上的三甲基化的减少，从而H3 K36 me 3-hMSH 2-hMSH 6-SKP 2复合物也减少。引人注目的是，染色体上的复合体占据被抑制，阻止了错配DNA修复。在降低Skp 2对与受损DNA结合的老化组蛋白H3的降解能力的同时，老化组蛋白修复受损。此外，受损DNA逃逸修复可导致微卫星不稳定性（MSI）和细胞周期相关基因的异常表达，从而触发肝癌的发生。本研究为HOTAIR通过下调肝癌干细胞中的SETD 2促进肿瘤发生提供了证据。
Long non-coding RNA HOTAIR predicts negative tumor prognosis and exhibits oncogenic activity. Herein, we demonstrate HOTAIR promotes human liver cancer stem cell malignant growth through downregulation of SETD2. Mechanistically, HOTAIR reduces the recuritment of the CREB, P300, RNA polII onto the SETD2 promoter region that inhibits SETD2 expression and its phosphorylation. Thereby, the SETD2 binding capacity to substrate histone H3 is weakened, triggering a reduction of trimethylation on histone H3 thirty-sixth lysine, and thereby the H3K36me3–hMSH2-hMSH6-SKP2 complex is also decreased. Strikingly, the complex occupancy on chromosome is depressed, preventing from mismatch DNA repair. While reducing the degradation capacity of Skp2 for aging histone H3 bound to damaged DNA, the aging histone repair is impaired. Furthermore, that the damaged DNA escaped to repair can causes microsatellite instability(MSI) and abnormal expression of cell cycle related genes that may trigger the hepatocarcinogenesis. This study provides evidence for HOTAIR to promote tumorigenesis via downregulating SETD2 in liver cancer stem cells.