Abstract
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.