LncRNA RUNX1-IT1 which is downregulated by hypoxia-driven histone deacetylase 3 represses proliferation and cancer stem-like properties in hepatocellular carcinoma cells
LncRNA RUNX1-IT1 which is downregulated by hypoxia-driven histone deacetylase 3 represses proliferation and cancer stem-like properties in hepatocellular carcinoma cells
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LncRNA RUNX1-IT1 被缺氧驱动的组蛋白脱乙酰酶 3 下调，抑制肝细胞癌细胞的增殖和癌症干细胞样特性
DOI：
10.1038/s41419-020-2274-x
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发表时间：
2020-02-05
影响因子：
9
通讯作者：
Liu, Qingguang
中科院分区：
文献类型：
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作者：
Sun, Liankang;Wang, Liang;Liu, Qingguang
肝细胞癌（HCC）的特点是缺氧微环境和高异质性和复发率，HCC中癌症干细胞（CSC）的存在可以很好地解释这两种病理特性。越来越多的证据表明，长链非编码RNA（lncRNA）参与肝癌的发生并维持肝癌细胞的干细胞性。然而，干细胞相关lncRNA在肝癌中的表达模式、调控机制和潜在作用尚不清楚。LncRNA RUNX 1-IT 1是RUNX 1的内含子转录物1，也称为21号染色体开放阅读框96（C21 orF 96）。尽管RUNX 1在不同疾病中的功能已被证实，但RUNX 1-IT 1在HCC中的功能及其可能的作用机制仍不清楚。在本研究中，我们证实了LncRNA RUNX 1-IT 1在GEO数据集、HCC样本中的表达降低，并且与不利的临床病理特征和不良预后相关。RUNX 1-IT 1在体外抑制肝癌细胞增殖、细胞周期进程、侵袭和肿瘤干化，并诱导凋亡。RUNX 1-IT 1的过表达损害肝癌细胞的生长、转移和干细胞样特征。在机制上，RUNX 1-IT 1直接结合miR-632，并作为竞争性内源性RNA促进miR-632靶基因GSK-3β的表达，随后调节HCC细胞中的WNT/β-catenin途径。此外，缺氧驱动的组蛋白去乙酰化酶3（HDAC 3），作为一种上游调控机制，是至关重要的下调RUNX 1-IT 1在肝癌。因此，lncRNA RUNX 1-IT 1作为缺氧的调节因子，可能成为攻克HCC的潜在治疗靶点。
Hepatocellular carcinoma (HCC) is characterised by a hypoxic microenvironment and a high rate of heterogeneity and recurrence, and the presence of cancer stem cells (CSCs) in HCC may well explain both of these pathological properties. There is mounting evidence that long non-coding RNAs (lncRNAs) participate in carcinogenesis and maintain cancer stemness of HCC cells. However, the expression modes, regulatory mechanisms and potential roles of stemness-related lncRNAs in HCC are still obscure. LncRNA RUNX1-IT1 is the intronic transcript 1 of the RUNX1, which is also known as chromosome 21 open-reading frame 96 (C21orF96). Although the functions of the RUNX1 have been identified in different diseases, the function and its potential mechanisms of the lncRNA RUNX1-IT1 in HCC still remains to be largely unknown. In this study, we verified that the expression of LncRNA RUNX1-IT1 was decreased in GEO data set, HCC samples and correlated with unfavourable clinicopathologic characteristics and poor prognosis. RUNX1-IT1 repressed HCC cell proliferation, cell cycle progression, invasion and cancer stemness and induced apoptosis in vitro. Overexpression of RUNX1-IT1 impaired the growth, metastasis and stem-like features of HCC cells in vivo. Mechanistically, RUNX1-IT1 directly bound to miR-632 and acted as competing endogenous RNA to facilitate the expression of the miR-632 target gene GSK-3β and subsequently modulate the WNT/β-catenin pathway in HCC cells. Furthermore, hypoxia-driven histone deacetylase 3 (HDAC3), as an upstream regulatory mechanism, was critical for the downregulation of RUNX1-IT1 in HCC. Thus, lncRNA RUNX1-IT1, as a regulator of hypoxia, may function as a potential therapeutic target for conquering HCC.