Rescue of the epigenetically silenced microRNA-493-5p inhibits cancer progression

Gailhouste L1, Liew LC1,2, Hatada I3 and Ochiya T1

  1. National Cancer Center Research Institute Tokyo, JAPAN.
  2. The University of Tokyo, JAPAN.
  3. Gunma University, Maebashi, JAPAN.

Alteration of microRNAs (miRNAs) has been widely reported in cancer. However, little is known about the mechanisms that lead to the abnormal expression of these small noncoding RNAs during tumorigenesis. Our group previously showed that DNA methylation is a major biological phenomenon that controls the expression of specific miRNAs, which are associated with the maintenance of a hepatospecific phenotype (Gailhouste et al., 2013 and 2018). In this new study, we aimed to identify potential tumor-suppressor miRNAs silenced by aberrant CpG methylation using a human hepatocellular carcinoma (HCC) cell model. Here, we highlighted a major tumor-suppressor miRNA, miR-493-5p, which was found to be silenced by DNA hypermethylation in HCC cells. Interestingly, knockdown of the DNA methyltransferase (DNMT) 1 enzyme was associated with the demethylation of miR-493-5p promoter region and restauration of its expression. Furthermore, we demonstrated that miR-493-5p rescue suppressed HCC cell proliferation, motility, and invasion in vitro. Next, we identified insulin-like growth factor 2 (IGF2) and miR-483-3p oncomir as direct targets of miR-493-5p. In addition, the silencing of these targets was able to mimic the effect of miR-493-5p overexpression in HCC cells. Remarkably, miR-493-5p reexpression promoted a significant anticancer response in vivo by repressing HCC tumor growth. In conclusion, our results demonstrate that miR-493-5p is epigenetically silenced by CpG hypermethylation in liver cancer cells. After rescue, this miRNA acts as a tumor-suppressor by inhibiting IGF2 and miR-483-3p expression. Combined, these findings suggest the therapeutic potential of miR-493-5p for the treatment of solid tumors.