Exploring the regulation of YAP and TAZ in antitubulin drug response and mammary tumorigenesis

Abstract

TAZ and YAP are transcriptional coactivators negatively regulated in the tumor suppressor (TS) Hippo pathway. TAZ and YAP play essential roles in tumorigenesis, epithelial mesenchymal transition (EMT) as well as cell resistances to different chemotherapeutic drugs such as the antitubulin drug Taxol. Although previous studies from the Yang Lab have shown that TAZ induces Taxol resistance through activation of downstream targets Cysteine rich 61 (Cyr61) and Connective Tissue Growth Factor (CTGF), the upstream regulations of YAP and TAZ during Taxol treatment is largely unknown. In this study, a Hippo independent negative regulation of YAP and TAZ is identified. In response to antitubulin drug treatments, Cyclin dependent kinase 1 (Cdk1) kinase can directly phosphorylate YAP and TAZ at multiple sites with SP/TP (S, serine; T, threonine; P, proline) motifs. The phosphorylation of YAP abolishes its interactions with transcription factor (TF) TEAD, whereas phosphorylation of TAZ by Cdk1 decreases the stability of TAZ. Our studies provide potential strategies and biomarkers to treat and predict antitubulin resistance. In addition to Cdk1, another kinase PIK3CB was identified as a positive regulator of TAZ/YAP. PIK3CB induces EMT and tumorigenesis by activating TAZ/YAP through inhibition of LATS. Collectively, the findings in our study provide another two novel regulators of TAZ and YAP in addition to the canonical Hippo pathway, which broadens our understanding of the molecular signaling network of the Hippo pathway. Furthermore, our research findings have significant implications for the prognosis and treatment of breast cancer patients in the future.