Transcriptional activation of S100A2 expression by HIF‐1α via binding to the hypomethylated hypoxia response elements in HCC cells

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers. Dysregulation of S100A2 has recently been found in many cancers including HCC. However, its regulatory mechanism in HCC remains poorly understood, especially in hypoxia. In this study, we found that S100A2 is upregulated and correlated with the clinicopathological features of HCC patients. Moreover, the elevated S100A2 showed worse overall survival. Functionally, S100A2 inhibition decreased the proliferation and migration of HepG2 cells. Interestingly, we found that HIF-1α directly binds to hypoxia response elements (HREs) of the S100A2 promoter region. S100A2 expression could be induced in an HIF-1α-dependent manner under hypoxia. Furthermore, S100A2 silencing significantly suppressed HCC cell proliferation and invasion under hypoxia. Mechanistically, pyrosequencing results showed that the hypomethylation status of CpG located in the HRE at the S100A2 promoter was correlated with S100A2 induction. Additionally, HIF-1α- mediated S100A2 activation was associated with TET2-related epigenetic inactivation. TET2 was enriched in the HRE of the S100A2 promoter in HepG2 cells. Finally, S100A2 methylation-related genes and pathways were analyzed. We found that the methylation of S100A2 is correlated with ANXA2, PPP1R15A, and FOS, which include in a hypoxia-related gene set from the GSEA database. Moreover, some EMT-related genes are associated with the methylation of S100A2 in HCC. Conclusively, our study thus uncovered a novel mechanism showing that hypoxia/HIF-1α signaling associated with DNA methylation enhances S100A2 expression in HCC. S100A2 may be useful as a target for facilitating novel diagnostic and therapeutic strategies in liver cancer.