LncBRM initiates YAP1 signalling activation to drive self-renewal of liver cancer stem cells.

Pingping Zhu,Buqing Ye,Yong Tian,Jiayi Wu,Ying Du,Guangxia Gao,Lei He,Guanling Huang,Zusen Fan,Yanying Wang,Benyu Liu

doi:10.1038/ncomms13608

Abstract

Liver cancer stem cells (CSCs) may contribute to the high rate of recurrence and heterogeneity of hepatocellular carcinoma (HCC). However, the biology of hepatic CSCs remains largely undefined. Through analysis of transcriptome microarray data, we identify a long noncoding RNA (lncRNA) called lncBRM, which is highly expressed in liver CSCs and HCC tumours. LncBRM is required for the self-renewal maintenance of liver CSCs and tumour initiation. In liver CSCs, lncBRM associates with BRM to initiate the BRG1/BRM switch and the BRG1-embedded BAF complex triggers activation of YAP1 signalling. Moreover, expression levels of lncBRM together with YAP1 signalling targets are positively correlated with tumour severity of HCC patients. Therefore, lncBRM and YAP1 signalling may serve as biomarkers for diagnosis and potential drug targets for HCC.

Highlights

Liver cancer stem cells (CSCs) may contribute to the high rate of recurrence and heterogeneity of hepatocellular carcinoma (HCC)
We define a highly transcribed long noncoding RNA (lncRNA) in liver CSCs that we call lncBRM (lncRNA for association with Brahma (BRM), gene symbol LINCR-0003), which associates with BRM and modulates the BRG1/BRM switch in the BRG1-associated factor (BAF) complex, leading to activation of YAP1 signalling and promotion of liver CSC self-renewal
We previously showed that an uncharacterized lncRNA lncTCF7 regulates the maintenance of liver CSCs through recruitment of the SWI/SNF complex to activate Wnt signalling

Summary

Introduction

Liver cancer stem cells (CSCs) may contribute to the high rate of recurrence and heterogeneity of hepatocellular carcinoma (HCC). Through analysis of transcriptome microarray data, we identify a long noncoding RNA (lncRNA) called lncBRM, which is highly expressed in liver CSCs and HCC tumours. In liver CSCs, lncBRM associates with BRM to initiate the BRG1/BRM switch and the BRG1-embedded BAF complex triggers activation of YAP1 signalling. Expression levels of lncBRM together with YAP1 signalling targets are positively correlated with tumour severity of HCC patients. How lncRNAs regulate the self-renewal of liver CSCs remains largely unknown. We define a highly transcribed lncRNA in liver CSCs that we call lncBRM (lncRNA for association with Brahma (BRM), gene symbol LINCR-0003), which associates with BRM and modulates the BRG1/BRM switch in the BRG1-associated factor (BAF) complex, leading to activation of YAP1 signalling and promotion of liver CSC self-renewal

Methods

Results

Conclusion