Long noncoding RNA LBCS inhibits self-renewal and chemoresistance of bladder cancer stem cells through epigenetic silencing of SOX2

Purpose: Chemoresistance and tumor relapse are the leading cause of deaths in bladder cancer patients. Bladder cancer stem cells (BCSCs) have been reported contribute to these pathological properties. However, the molecular mechanisms underlying their self-renewal and chemoresistance remain largely unknown. In the current study, a novel lncRNA-LBCS has been identified and explored in BCSCs. Experimental Design: Firstly, we establish BCSCs model and explore the BCSCs associated lncRNAs by transcriptome microarray. The expression and clinical features of lnc-LBCS are analyzed in three independent large-scale cohorts. The functional role and mechanism of lnc-LBCS are further investigated by gain and loss of function assays in vitro and in vivo. Results: Lnc-LBCS is significantly downregulated in BCSCs and cancer tissues, and correlates with tumor grade, chemotherapy response and prognosis. Moreover, lnc-LBCS markedly inhibits self-renewal, chemoresistance and tumor initiation of BCSCs both in vitro and in vivo. Mechanistically, lnc-LBCS directly binds to hnRNPK and EZH2, and serves as a scaffold to induce the formation of this complex to repress SOX2 transcription via mediating histone H3 lysine 27 tri-methylation (H3K27me3). SOX2 is essential for self-renewal and chemoresistance of BCSCs, and correlates with the clinical severity and prognosis of bladder cancer patients. Conclusions: As a novel regulator, lnc-LBCS plays an important tumor suppressor role in BCSCs self-renewal and chemoresistance, contributing to weak tumorigenesis and enhanced chemosensitivity. The lnc-LBCS-hnRNPK-EZH2-SOX2 regulatory axis may represent a therapeutic target for clinical intervention in chemoresistant bladder cancer.

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