Lnc RNA wires up Hippo and Hedgehog signaling to reprogramme glucose metabolism

The Hippo pathway plays essential roles in organ size control and cancer prevention via restricting its downstream effector, Yes‐associated protein ( YAP ). Previous studies have revealed an oncogenic function of YAP in reprogramming glucose metabolism, while the underlying mechanism remains to be fully clarified. Accumulating evidence suggests long noncoding RNA s (lnc RNA s) as attractive therapeutic targets, given their roles in modulating various cancer‐related signaling pathways. In this study, we report that lnc RNA breast cancer anti‐estrogen resistance 4 ( BCAR 4) is required for YAP ‐dependent glycolysis. Mechanistically, YAP promotes the expression of BCAR 4, which subsequently coordinates the Hedgehog signaling to enhance the transcription of glycolysis activators HK 2 and PFKFB 3. Therapeutic delivery of locked nucleic acids ( LNA s) targeting BCAR 4 attenuated YAP ‐dependent glycolysis and tumor growth. The expression levels of BCAR 4 and YAP are positively correlated in tissue samples from breast cancer patients, where high expression of both BCAR 4 and YAP is associated with poor patient survival outcome. Taken together, our study not only reveals the mechanism by which YAP reprograms glucose metabolism, but also highlights the therapeutic potential of targeting YAP ‐ BCAR 4‐glycolysis axis for breast cancer treatment. image Yes‐associated protein promotes cancer formation by reprogramming glucose metabolism. A long noncoding RNA BCAR 4 is a key downstream effector of YAP , in regulation of glycolysis and tumorigenesis via GLI 2‐mediated expression of key glycolytic enzymes. BCAR4 is a direct transcriptional target of YAP. BCAR4 promotes glycolysis by increasing the expression of HK2 and PFKFB3. GLI2 activation is required for the expression of glycolytic enzymes downstream of BCAR4 High YAP and BCAR4 expression levels positively correlate in breast cancer patient samples and are linked to poor clinical outcomes. Inhibition of BCAR4 via Locked Nucleic Acids (LNAs) attenuated YAP‐dependent glycolysis and tumor growth.