Wang Jun, Liu Runkun, Wang Yufeng, Mo Huanye, Niu Yongshen, Xu Qiuran, Liu Qingguang
Department of Emergency, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
J Cancer. 2021 Jul 3;12(17):5320-5330. doi: 10.7150/jca.58697. eCollection 2021.
Hepatocellular carcinoma (HCC) is one of the most common solid tumors globally. Our previous studies revealed that miR-627-5p suppresses HCC progression via targeting BCL3/CCND1 pathway. However, the molecular mechanism by which miR-627-5p was downregulated in HCC remains to be further elucidated. As a hallmark of solid tumors, hypoxia results in the rapid growth, strongly potential invasion and high frequent metastasis of cancer cells. Hypoxia-inducible factors (HIFs), mainly including HIF-1 and HIF-2, are the classical transcription factors which mediate hypoxia-related gene transcription. Here, we demonstrated that miR-627-5p was repressed by hypoxia in a HIF-1-dependent manner in HCC cells. But HIF-1 regulated miR-627-5p expression not directly through the hypoxia-response element (HRE) sites of MIR627 gene. In contrast, histone deacetylase 3 (HDAC3) was identified as a HIF-1 target gene, and the occupancy of HIF-1 to HRE site was essential for hypoxia-mediated HDAC3 induction. And upregulated HDAC3 was closely related to the malignant clinical and pathological characteristics and worse prognosis of HCC. Furthermore, HDAC3-mediated histone deacetylation in promoter region of MIR627 was critical for hypoxia-mediated miR-627-5p repression. And miR-627-5p mediated the effects of hypoxic condition on HCC progression. Thus, this study has revealed that miR-627-5p was repressed by hypoxia under the mediation of HDAC3 in HCC, and there existed a HIF-1α/HDAC3/miR-627-5p/BCL3/CCND1 signal pathway in HCC.
肝细胞癌（HCC）是全球最常见的实体瘤之一。我们之前的研究表明，miR-627-5p通过靶向BCL3/CCND1通路抑制HCC进展。然而，miR-627-5p在HCC中下调的分子机制仍有待进一步阐明。作为实体瘤的一个标志，缺氧导致癌细胞快速生长、强烈的侵袭潜能和高频率转移。缺氧诱导因子（HIFs），主要包括HIF-1和HIF-2，是介导缺氧相关基因转录的经典转录因子。在此，我们证明miR-627-5p在HCC细胞中以HIF-1依赖的方式被缺氧抑制。但HIF-1并非直接通过MIR627基因的缺氧反应元件（HRE）位点调节miR-627-5p的表达。相反，组蛋白去乙酰化酶3（HDAC3）被鉴定为HIF-1靶基因，HIF-1对HRE位点的占据对于缺氧介导的HDAC3诱导至关重要。并且HDAC3上调与HCC的恶性临床和病理特征及较差预后密切相关。此外，HDAC3介导的MIR627启动子区域组蛋白去乙酰化对于缺氧介导的miR-627-5p抑制至关重要。并且miR-627-5p介导了缺氧条件对HCC进展的影响。因此，本研究揭示了在HCC中miR-627-5p在HDAC3介导下被缺氧抑制，且HCC中存在HIF-1α/HDAC3/miR-627-5p/BCL3/CCND1信号通路。
