HN1L-mediated transcriptional axis AP-2γ/METTL13/TCF3-ZEB1 drives tumor growth and metastasis in hepatocellular carcinoma

Cell Death Differ. 2019 Nov;26(11):2268-2283. doi: 10.1038/s41418-019-0301-1. Epub 2019 Feb 18.

Abstract

Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies and lacks targeted therapies. Here, we reported a novel potential therapeutic target hematological and neurological expressed 1 like (HN1L) in HCC. First, HCC tissue microarray analysis showed that HN1L was frequently up-regulated in cancer tissues than that in normal liver tissues, which significantly associated with tumor size, local invasion, distant metastases, and poor prognosis for HCC patients. Functional studies demonstrated that ectopic expression of HN1L could increase cell growth, foci formation in monolayer culture, colony formation in soft agar and tumorigenesis in nude mice. In addition, HN1L could also promote HCC metastasis by inducing epithelial-mesenchymal transition. Inversely, silencing HN1L expression with shRNA could effectively attenuate its oncogenic function. We further showed that HN1L transcriptionally up-regulated methyltransferase like 13 (METTL13) gene in an AP-2γ dependent manner, which promoted cell proliferation and metastasis by up-regulating TCF3 and ZEB1. Importantly, administration of lentivirus-mediated shRNA interfering HN1L expression could inhibit tumorigenesis and metastasis in mice. Collectively, HN1L-mediated transcriptional axis AP-2γ/METTL13/TCF3-ZEB1 promotes HCC growth and metastasis representing a promising therapeutic target in HCC treatment.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Carcinoma, Hepatocellular / pathology*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation / physiology
  • Cell Transformation, Neoplastic / pathology
  • Epithelial-Mesenchymal Transition / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Liver Neoplasms / pathology*
  • Methyltransferases / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Neoplasm Metastasis / pathology
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Transcription Factor AP-2 / metabolism*
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • JPT1 protein, human
  • JPT2 protein, human
  • Microtubule-Associated Proteins
  • RNA, Small Interfering
  • TCF3 protein, human
  • TFAP2C protein, human
  • Transcription Factor AP-2
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1
  • EEF1AKNMT protein, human
  • Methyltransferases