lncRNA HotairM1 Depletion Promotes Self-Renewal of Cancer Stem Cells through HOXA1-Nanog Regulation Loop.
lncRNA HotairM1 Depletion Promotes Self-Renewal of Cancer Stem Cells through HOXA1-Nanog Regulation Loop.
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lncRNA HotairM1 消耗通过 HOXA1-Nanog 调节环促进癌症干细胞的自我更新
DOI：
10.1016/j.omtn.2020.09.008
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发表时间：
2020-12-04
期刊：
影响因子：
--
通讯作者：
Fan X
中科院分区：
文献类型：
--
作者：
Li F;Xu Y;Xu X;Ge S;Zhang F;Zhang H;Fan X
在癌细胞中，干性的获得可能对肿瘤的发生、侵袭性和临床结果具有深远的影响。然而，维持癌症干细胞样细胞（CSCs）自我更新的分子机制仍然难以捉摸。在这里，基于转录组测序分析，我们确定了一个长的非编码RNA（lncRNA）命名为HotairM 1，这是弱表达在人类结直肠癌和葡萄膜黑色素瘤，和一个低得多的表达在相应的CSC。我们的研究结果表明，HotairM 1缺失可以促进CSC自我更新和肿瘤增殖。从机制上讲，HotairM 1将EZH 2和SUZ 12募集到其靶基因HOXA 1的启动子，导致组蛋白H3 K27三甲基化和HOXA 1的表观遗传沉默。HOXA 1的沉默随后诱导Nanog基因增强子位点的H3 K27乙酰化以上调其表达。Nanog的富集可以进一步抑制HOXA 1的表达，形成一个相互调节的环，增强了干性维持效果。总之，我们的研究结果揭示了一个基于lncRNA的调控环，它维持了CSC的自我更新，这突出了HotairM 1通过HOXA 1-Nanog信号环在CSC发育中的关键作用。IncRNA HotairM 1的敲除可通过抑制邻近基因HOXA 1的表达促进CSC的自我更新和随后的肿瘤增殖和繁殖。HOXA 1可能通过抑制Nanog的表达而抑制CSC的干性维持。
In cancer cells, a gain of stemness may have profound implications for tumor initiation, aggressiveness, and clinical outcome. However, the molecular mechanisms underlying the self-renewal maintenance of cancer stem-like cells (CSCs) remain elusive. Here, based on analysis of transcriptome sequencing, we identified a long noncoding RNA (lncRNA) named HotairM1, which is weakly expressed in human colorectal carcinoma and uveal melanoma, and a much lower expression in corresponding CSCs. Our results showed that HotairM1 depletion could promote CSC self-renewal and tumor propagation. Mechanistically, HotairM1 recruit EZH2 and SUZ12 to the promoter of its target gene HOXA1, leading to histone H3K27 trimethylation and epigenetic silencing of HOXA1. The silence of HOXA1 subsequently induces the H3K27 acetylation at the enhancer site of Nanog gene to upregulate its expression. The enrichment of Nanog could further inhibit HOXA1 expression, forming a reciprocal regulation loop augmenting the stemness maintaining effect. In summary, our results revealed a lncRNA-based regulatory loop that sustains self-renewal of CSCs, which highlights the critical role of HotairM1 in CSC development through the HOXA1-Nanog signaling loop. Knockdown of lncRNA HotairM1 could promote self-renewal of CSCs and subsequent tumor proliferation and propagation through inhibiting neighbor gene HOXA1 expression. HOXA1 would repress stemness maintenance of CSC through inhibiting Nanog expression.
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影响因子：
16.8
作者：
Højfeldt JW;Laugesen A;Willumsen BM;Damhofer H;Hedehus L;Tvardovskiy A;Mohammad F;Jensen ON;Helin K
通讯作者：
Helin K
DOI：
10.1007/978-1-62703-227-8_16
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Boiko, Alexander D
通讯作者：
Boiko, Alexander D
影响因子：
11.8
作者：
Krishnamurthy N;Kurzrock R
通讯作者：
Kurzrock R
影响因子：
4.7
作者：
Bahmad HF;Cheaito K;Chalhoub RM;Hadadeh O;Monzer A;Ballout F;El-Hajj A;Mukherji D;Liu YN;Daoud G;Abou-Kheir W
通讯作者：
Abou-Kheir W
影响因子：
50.3
作者：
Hu X;Feng Y;Zhang D;Zhao SD;Hu Z;Greshock J;Zhang Y;Yang L;Zhong X;Wang LP;Jean S;Li C;Huang Q;Katsaros D;Montone KT;Tanyi JL;Lu Y;Boyd J;Nathanson KL;Li H;Mills GB;Zhang L
通讯作者：
Zhang L