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

Abstract

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.

• Authors: Zhenzhen Chen, Yanfeng Gao, Lintong Yao, Yating Liu, Lan Huang, Zhongyi Yan, Wenshan Zhao, Pingping Zhu, Haibo Weng
• Journal: Oncogene (Oncogene) Vol. 37 Issue 23 Pg. 3098-3112 (06 2018) ISSN: 1476-5594 [Electronic] England
• PMID: 29535420 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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