The histone deacetylase 4/SP1/microrna‐200a regulatory network contributes to aberrant histone acetylation in hepatocellular carcinoma

As an important epigenetic mechanism, histone acetylation modulates the transcription of many genes and plays important roles in hepatocellular carcinoma (HCC). Aberrations in histone acetylation have been observed in HCC, but the factors that contribute to the aberrations have not been fully elucidated. MicroRNAs (miRNAs), which are noncoding RNAs that regulate gene expression, are involved in important epigenetic mechanisms. In this study, we determined that miR‐200a and the level of histone H3 acetylation at its promoter were reduced in human HCC tissues in comparison with adjacent noncancerous hepatic tissues. Furthermore, our results suggested that the histone deacetylase 4 (HDAC4) inhibited the expression of miR‐200a and its promoter activity and reduced the histone H3 acetylation level at the mir‐200a promoter through a Sp1‐dependent pathway. Interestingly, we observed that the miR‐200a directly targeted the 3′‐untranslated region of the HDAC4 messenger RNA and repressed expression of HDAC4. Therefore, miR‐200a ultimately induced its own transcription and increased the histone H3 acetylation level at its own promoter. Through targeting HDAC4, miR‐200a also induced the up‐regulation of total acetyl‐histone H3 levels and increased the histone H3 acetylation level at the p21WAF/Cip1 promoter. Finally, we determined that miR‐200a inhibited the proliferation and migration of HCC cells in vivo and in vitro. Conclusion: Our findings suggest that the HDAC4/Sp1/miR‐200a regulatory network induces the down‐regulation of miR‐200a and the up‐regulation of HDAC4 in HCC. As a result, down‐regulation of miR‐200a enhances the proliferation and migration of HCC cells and induces aberrant histone acetylation in HCC. These findings highlight a potential therapeutic approach in targeting the HDAC4/Sp1/miR‐200a regulatory network for the treatment of HCC. (HEPATOLOGY 2011