Pharmacological or transcriptional inhibition of both HDAC1 and 2 leads to cell cycle blockage and apoptosis via p21Waf1/Cip1 and p19INK4d upregulation in hepatocellular carcinoma.

Abstract

OBJECTIVES:

Histone deacetylases (HDACs) are commonly dysregulated in cancer and represent promising therapeutic targets. However, global HDAC inhibitors have shown limited efficacy in the treatment of solid tumours, including hepatocellular carcinoma (HCC). In this study, we investigated the therapeutic effect of selectively inhibiting HDAC1 and 2 in HCC.

METHODS:

HDAC1 inhibitor Tacedinaline (CI994), HDAC2 inhibitor Santacruzamate A (CAY10683), HDAC1/2 common inhibitor Romidepsin (FK228) and global HDAC inhibitor Vorinostat (SAHA) were used to treat HCC cells. Cell cycle, apoptosis and the protein levels of CDKs and CDKNs were performed to evaluate HCC cell growth. Inhibition of HDAC1/2 by RNAi was further investigated.

RESULTS:

Combined inhibition of HDAC1/2 led to HCC cell morphology changes, growth inhibition, cell cycle blockage and apoptosis in vitro and suppressed the growth of subcutaneous HCC xenograft tumours in vivo. p21Waf1/Cip1 and p19INK4d , which play roles in cell cycle blockage and apoptosis induction, were upregulated. Inhibition of HDAC1/2 by siRNA further demonstrated that HDAC1 and 2 cooperate in blocking the cell cycle and inducing apoptosis via p19INK4d and p21Waf1/Cip1 upregulation. Finally, H3K18, H3K56 and H4K12 in the p19INK4d and p21Waf1/Cip1 promoter regions were found to be targets of HDAC1/2.

CONCLUSIONS:

Pharmacological or transcriptional inhibition of HDAC1/2 increases p19INK4d and p21Waf1/Cip1 expression, decreases CDK expression and arrests HCC growth. These results indicated a potential pharmacological mechanism of selective HDAC1/2 inhibitors in HCC therapy.

• Authors: Hengyu Zhou, Ying Cai, Dina Liu, Menghui Li, Yu Sha, Wenlu Zhang, Kai Wang, Jianping Gong, Ni Tang, Ailong Huang, Jie Xia
• Journal: Cell proliferation (Cell Prolif) Vol. 51 Issue 3 Pg. e12447 (Jun 2018) ISSN: 1365-2184 [Electronic] England
• PMID: 29484736 (Publication Type: Journal Article)
• Copyright: © 2018 John Wiley & Sons Ltd.

Chemical References

• Antineoplastic Agents
• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p19
• Cyclin-Dependent Kinase Inhibitor p21
• Depsipeptides
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Vorinostat
• romidepsin
• HDAC1 protein, human
• HDAC2 protein, human
• Histone Deacetylase 1
• Histone Deacetylase 2

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Carcinoma, Hepatocellular (drug therapy, enzymology)
• Cell Cycle Checkpoints (drug effects)
• Cyclin-Dependent Kinase Inhibitor p19 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Depsipeptides (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Hep G2 Cells
• Histone Deacetylase 1 (metabolism)
• Histone Deacetylase 2 (metabolism)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Hydroxamic Acids (pharmacology)
• Liver Neoplasms (drug therapy, enzymology)
• Mice, Nude
• Transcription, Genetic
• Up-Regulation
• Vorinostat
• Xenograft Model Antitumor Assays