Highly expressed histone deacetylase 5 promotes the growth of hepatocellular carcinoma cells by inhibiting the TAp63-maspin pathway

[摘要] Aberrant expression of histone deacetylases (HDACs) has been detected in a variety of cancers, which disrupts the balance between cell proliferation and apoptosis in favor of continuous growth. A previous study demonstrated that HDAC5 contributes to the proliferation of hepatocellular carcinoma (HCC) cells, but a clear understanding of the mechanism has not yet been provided. In the present work, we found that the levels of HDAC5 were significantly higher in HCC tissues and cells than in adjacent tissues and normal hepatic cells. In addition, knockdown of HDAC5 attenuated the proliferation of Hep3B and HepG2 cells. Through profiling the expressions of proliferation and apoptosis-related genes in Hep3B cells following HDAC5 knockdown, p63 and maspin were found obviously up-regulated in HDAC5-deprived cells compared with the control. Further investigations confirmed that HDAC5 knockdown induced TAp63 expression in HCC cells, accompanied with increased H3K9 acetylation at the TAp63 promoter. Overexpression of TAp63 led to proliferation inhibition by inducing cell cycle arrest. Additionally, TAp63 that was required for the maspin upregulation resulted from HDAC5 knockdown. Phenotype experiments showed that interrupting either TAp63 or maspin recovered the proliferative and tumorigenic capabilities of HCC cells with HDAC5 knockdown. Clinical analysis showed that HDAC5 was negatively correlated with TAp63 and maspin in HCC tissues. In addition, a high level of HDAC5 as well as a low level of TAp63 or maspin predicted poor survival in HCC patients. Taken together, this study proposes the existence of an aberrant HDAC5-TAp63-maspin pathway conferring HCC progression through proliferation induction, which suggests novel intervention targets for the disease.

[学科分类] 肿瘤学

[关键词] Histone deacetylase 5 (HDAC5);p63;mammary serpin (maspin);hepatocellular carcinoma (HCC);proliferation