Nuclear phosphoinositide signaling promotes YAP/TAZ-TEAD transcriptional activity in breast cancer

The Hippo pathway effectors Yes-associated protein 1 (YAP) and its homolog TAZ are transcriptional coactivators that control gene expression by binding to TEA domain (TEAD) family transcription factors. The YAP/TAZ-TEAD complex is a key regulator of cancer-specific transcriptional programs, which promote tumor progression in diverse types of cancer, including breast cancer. Despite intensive efforts, the YAP/TAZ-TEAD complex in cancer has remained largely undruggable due to an incomplete mechanistic understanding. Here, we report that nuclear phosphoinositides function as cofactors that mediate the binding of YAP/TAZ to TEADs. The enzymatic products of phosphoinositide kinases PIPKI alpha and IPMK, including phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate (P(I3,4,5)P3), bridge the binding of YAP/TAZ to TEAD. Inhibiting these kinases or the association of YAP/TAZ with PI(4,5)P2 and PI(3,4,5)P3 attenuates YAP/TAZ interaction with the TEADs, the expression of YAP/TAZ target genes, and breast cancer cell motility. Although we could not conclusively exclude the possibility that other enzymatic products of IPMK such as inositol phosphates play a role in the mechanism, our results point to a previously unrecognized role of nuclear phosphoinositide signaling in control of YAP/TAZ activity and implicate this pathway as a potential therapeutic target in YAP/TAZ-driven breast cancer. The YAP-TEAD transcriptional regulators play a pivotal role in tumorigenesis, but activation of this pathway remains incompletely understood at the molecular level. This study implicates nuclear inositol phospholipids as molecular glue mediating YAP-TEAD interaction, required for full activation of the YAP-TEAD complex in breast cancer.YAP binds to phosphoinositide species via a polybasic motif located in its TEAD-binding domain. Phosphoinositides generated by lipid kinases, i.e., PIPKIa and IPMK, facilitate the binding of YAP to TEAD. Inhibition of PIPKIa and IPMK, or blockade of phosphoinositide binding to YAP, diminishes the expression of YAP target genes. The phosphoinositide-driven enhancement of YAP-TEAD complex formation promotes breast cancer cell motility. Phosphoinositide products of lipid kinases PIPKIa and IPMK bind to the transcriptional co-activator YAP and enhance its interaction with the transcription factor TEAD.