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

被引：68

作者：

Chen, Zhenzhen ^{[1
]}

Gao, Yanfeng ^{[1
,2
]}

Yao, Lintong ^{[1
]}

Liu, Yating ^{[1
]}

Huang, Lan ^{[3
]}

Yan, Zhongyi ^{[1
]}

Zhao, Wenshan ^{[1
]}

Zhu, Pingping ^{[1
]}

Weng, Haibo ^{[1
]}

机构：

[1] Zhengzhou Univ, Sch Life Sci, Zhengzhou 450001, Henan, Peoples R China

[2] Collaborat Innovat Ctr New Drug Res & Safety Eval, Zhengzhou 450001, Henan, Peoples R China

[3] Zhengzhou Univ, Affiliated Hosp 1, Zhengzhou 450052, Henan, Peoples R China

来源：

ONCOGENE | 2018年 / 37卷 / 23期

基金：

中国国家自然科学基金;

关键词：

CANCER STEM-CELLS; SIDE POPULATION; WNT; GENE; MECHANISMS;

D O I：

10.1038/s41388-018-0203-6

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Liver tumor-initiating cells (TICs), the drivers for liver tumorigenesis, accounts for liver tumor initiation, metastasis, drug resistance and relapse. Wnt/beta-catenin signaling pathway emerges as a critical modulator in liver TIC self-renewal. However, the molecular mechanism of Wnt/beta-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 nonTICs and drives the self-renewal of liver TICs through lncFZD6-BRG1-FZD6-dependent manner. Through FZD6 transcriptional regulation in cis, lncFZD6 activates Wnt/beta-catenin signaling in liver TICs. LncFZD6-BRG1-Wnt5A/beta-catenin pathway can serve as a target for liver TIC elimination. Altogether, lncFZD6 promotes Wnt/beta-catenin activation and liver TIC self-renewal through BRG1-dependent FZD6 expression.

引用

页码：3098 / 3112

页数：15

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