Enhancer of zeste homolog 2 promotes hepatocellular cancer progression and chemoresistance by enhancing protein kinase B activation through microRNA-381-mediated SET domain bifurcated 1

Bioengineered. 2022 Mar;13(3):5737-5755. doi: 10.1080/21655979.2021.2023792.

Abstract

Metastasis and chemoresistance are the leading causes of death in patients with hepatocellular carcinoma (HCC). microRNAs (miRNAs or miRs) may be useful as diagnostic, therapeutic and prognostic markers for HCC. In this study, we set out to investigate the possible role of miR-381 in HCC development and chemoresistance along with the related mechanism. Microarray-based gene expression profiling was carried out to analyze the expression of SET domain bifurcated 1 (SETDB1) and histone methyltransferase enhancer of zeste homolog 2 (EZH2) followed by validation in clinical HCC tissues and cells. The potential binding between miR-381 and SETDB1 was found and verified. Then, the role of SETDB1 in HCC in relation to miR-381 and protein kinase B (AKT) pathway was explored through gain- and loss-of-function approaches. After expression determination of EZH2, SETDB1, miR-381, and AKT pathway-related factors, their reactions were analyzed and their functional roles in HCC progression and chemoresistance were investigated in vitro and in vivo. SETDB1 was aberrantly upregulated in clinical HCC tissues and cells. This upregulation activated AKT pathway by promoting its tri-methylation on K64. SETDB1 promoted the proliferation, migration and chemoresistance through the AKT pathway in HCC cells. In a xenograft mouse model, SETDB1 promoted HCC cell tumorigenesis in vivo by activating the AKT pathway. Furthermore, EZH2 suppressed miR-381 by catalyzing the activity of H3K27me3 on its promoter region. In conclusion, EZH2 suppressed miR-381 expression by promoting H3K27me3 activity on its promoter region to facilitate SETDB1 expression, thereby activating the AKT pathway to promote hepatocarcinogenesis and chemoresistance.

Keywords: AKT pathway; Hepatocellular cancer; SET domain bifurcated 1; chemoresistance; enhancer of zeste homolog 2; microRNA-381.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Carcinoma, Hepatocellular* / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Drug Resistance, Neoplasm / genetics
  • Enhancer of Zeste Homolog 2 Protein* / genetics
  • Enhancer of Zeste Homolog 2 Protein* / metabolism
  • Gene Expression Regulation, Neoplastic
  • Histone-Lysine N-Methyltransferase* / genetics
  • Histone-Lysine N-Methyltransferase* / metabolism
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Liver Neoplasms* / metabolism
  • Mice
  • Mice, Nude
  • MicroRNAs* / genetics
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism

Substances

  • Histones
  • MIRN381 microRNA, human
  • MicroRNAs
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Histone-Lysine N-Methyltransferase
  • SETDB1 protein, human
  • Proto-Oncogene Proteins c-akt

Grants and funding

This study was supported by the plan to the introduction of clinical medical expert teams of Xuzhou city [2018TD011].