A feed-forward loop between lncARSR and YAP activity promotes expansion of renal tumour-initiating cells.

Le Qu,Anbang Wang,Zhipeng Xu,Feng Liu,Bing Liu,Yinghao Sun,Yaoming Li,Yi Bao,Cheng Chen,Linhui Wang,Jiayi Liu,Zhenjie Wu,Xiaoyuan Chu,Zhengyu Zhang,Dengshuang Wu

doi:10.1038/ncomms12692

Abstract

Renal tumour-initiating cells (T-ICs) contribute to tumorigenesis, progression and drug resistance of renal cell carcinoma (RCC). However, the underlying mechanism for the propagation of renal T-ICs remains unclear. Here we show that long non-coding RNA lncARSR is upregulated in primary renal T-ICs and associated with a poor prognosis of clear cell RCCs (ccRCC). Knockdown of lncARSR attenuates the self-renewal, tumorigenicity and metastasis of renal T-ICs. Conversely, forced lncARSR expression enhances T-IC properties of RCC cells. Mechanistically, the binding of lncARSR to YAP impedes LATS1-induced YAP phosphorylation and facilitates YAP nuclear translocation. Reciprocally, YAP/TEAD promotes lncARSR transcription, thus forming a feed-forward circuit. The correlation between lncARSR and YAP is validated in a ccRCC cohort, where the combination of these two parameters exhibits improved prognostic accuracy. Our findings indicate that lncARSR plays a critical role in renal T-ICs propagation and may serve as a prognostic biomarker and potential therapeutic target.

Highlights

Renal tumour-initiating cells (T-ICs) contribute to tumorigenesis, progression and drug resistance of renal cell carcinoma (RCC)
Clinical investigation confirms the correlation between lncARSR and Yes-associated protein (YAP), and demonstrates the value of combining lncARSR and YAP to improve the prognostic accuracy for RCC patients
Knockdown of LATS restored the self-renewal capacity and the expression of pluripotent transcription factors in lncARSR-knockdown spheres (Fig. 6i,j and Supplementary Fig. 6i). These results demonstrated that lncARSR–YAP interaction prevented the phosphorylation of YAP by LATS1 and facilitated YAP nuclear translocation to promote renal T-IC properties

Summary

Introduction

Renal tumour-initiating cells (T-ICs) contribute to tumorigenesis, progression and drug resistance of renal cell carcinoma (RCC). We show that long non-coding RNA lncARSR is upregulated in primary renal T-ICs and associated with a poor prognosis of clear cell RCCs (ccRCC). The expression signature of stem cell[26,27,28] or targets of Nanog, Oct[4], Sox[2] and c-Myc (NOSM) in human ESCs29–31 were significantly enriched in our mRNA profile of sunitinib-resistant RCC cells (GSE69535) (Supplementary Fig. 1a), prompting us to explore the role of lncARSR in renal T-ICs. In this study, we first find that lncARSR is highly expressed in primary renal T-ICs and predicts poor prognosis. By using loss-of-function analysis in T-ICs and gain-of-function analysis in RCC cells, we demonstrate that lncARSR promotes the selfrenewal capacity, tumorigenicity and metastasis of renal T-ICs. Further mechanism study reveals that lncARSR interacts with Yes-associated protein (YAP) to block its phosphorylation by LATS1, facilitating YAP nuclear translocation. We discover that lncARSR promotes the expansion of renal T-ICs via interacting with YAP

Methods

Results

Conclusion