CCR7 preservation via histone deacetylase inhibition promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells

Exp Cell Res. 2018 Oct 1;371(1):231-237. doi: 10.1016/j.yexcr.2018.08.015. Epub 2018 Aug 11.

Abstract

The effects of Histone deacetylase (HDAC) inhibition on epithelial-mesenchymal transition (EMT) differs in various types of cancers. However, its function in hepatocellular carcinoma (HCC) is not well-explored. In this study, we investigated the effect of HDAC inhibition on EMT in HCC cells by using trichostatin A (TSA) and valproic acid (VPA). The results showed that TSA/VPA significantly induced EMT phenotype, as demonstrated by the decreased level of E-cadherin, increased level of N-cadherin, vimentin, Twist and snail, and enhanced capacity of cell migration and invasion. In addition, CCR7 was speculated and confirmed as a function target of HDAC inhibition. CCR7 promotes the progression of HCC and is associated with poor survival. Knockdown of CCR7 significantly attenuated the effect of TSA on EMT. Moreover, our results demonstrated that HDAC inhibition up-regulates CCR7 via reversing the promoter hypoacetylation and increasing CCR7 transcription. Taken together, our study has identified the function of HDAC in EMT of HCC and suggested a novel mechanism through which TSA/VPA exerts its carcinogenic roles in HCC. HDAC inhibitors require careful caution before their application as new anticancer drugs.

Keywords: CCR7; Epithelial-mesenchymal transition; Hepatocellular carcinoma; Histone deacetylase.

MeSH terms

  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Cadherins / genetics
  • Cadherins / metabolism
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Epithelial-Mesenchymal Transition / drug effects*
  • Epithelial-Mesenchymal Transition / genetics
  • Gene Expression Regulation, Neoplastic*
  • Hep G2 Cells
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology
  • Neoplasm Staging
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Promoter Regions, Genetic
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, CCR7 / antagonists & inhibitors
  • Receptors, CCR7 / genetics*
  • Receptors, CCR7 / metabolism
  • Signal Transduction
  • Snail Family Transcription Factors / genetics
  • Snail Family Transcription Factors / metabolism
  • Survival Analysis
  • Twist-Related Protein 1 / genetics
  • Twist-Related Protein 1 / metabolism
  • Valproic Acid / pharmacology
  • Vimentin / genetics
  • Vimentin / metabolism

Substances

  • Antigens, CD
  • CCR7 protein, human
  • CDH2 protein, human
  • Cadherins
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Nuclear Proteins
  • RNA, Small Interfering
  • Receptors, CCR7
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • TWIST1 protein, human
  • Twist-Related Protein 1
  • VIM protein, human
  • Vimentin
  • trichostatin A
  • Valproic Acid