LncFZD6 initiates Wnt/β-catenin and liver TIC self-renewal through BRG1-mediated FZD6 transcriptional activation

Oncogene. 2018 Jun;37(23):3098-3112. doi: 10.1038/s41388-018-0203-6. Epub 2018 Mar 14.


Liver tumor-initiating cells (TICs), the drivers for liver tumorigenesis, accounts for liver tumor initiation, metastasis, drug resistance and relapse. Wnt/β-catenin signaling pathway emerges as a critical modulator in liver TIC self-renewal. However, the molecular mechanism of Wnt/β-catenin initiation in liver tumorigenesis and liver TICs is still elusive. Here, we examined the expression pattern of 10 Wnt receptors (FZD1-FZD10), and found only FZD6 is overexpressed along with liver tumorigenesis. What's more, a divergent lncRNA of FZD6, termed lncFZD6, is also highly expressed in liver cancer and liver TICs. LncFZD6 drives liver TIC self-renewal and tumor initiation capacity through FZD6-dependent manner. LncFZD6 interacts with BRG1-embedded SWI/SNF complex and recruits it to FZD6 promoter, and thus drives the transcriptional initiation of FZD6 by chromatin remodeling. WNT5A, a ligand of FZD6, is highly expressed in liver non-TICs and drives the self-renewal of liver TICs through lncFZD6-BRG1-FZD6-dependent manner. Through FZD6 transcriptional regulation in cis, lncFZD6 activates Wnt/β-catenin signaling in liver TICs. LncFZD6-BRG1-Wnt5A/β-catenin pathway can serve as a target for liver TIC elimination. Altogether, lncFZD6 promotes Wnt/β-catenin activation and liver TIC self-renewal through BRG1-dependent FZD6 expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • Female
  • Frizzled Receptors / genetics*
  • Frizzled Receptors / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Male
  • Mice, Inbred BALB C
  • Middle Aged
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • RNA, Long Noncoding / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation
  • Wnt-5a Protein / metabolism*
  • Xenograft Model Antitumor Assays
  • beta Catenin / metabolism*


  • CTNNB1 protein, human
  • FZD6 protein, human
  • Frizzled Receptors
  • Nuclear Proteins
  • RNA, Long Noncoding
  • Transcription Factors
  • WNT5A protein, human
  • Wnt-5a Protein
  • beta Catenin
  • SMARCA4 protein, human
  • DNA Helicases