Heat shock protein 27 inhibits the Hippo tumor suppressor pathway by facilitating MST1 proteasomal degradation

Heat shock protein 27 (Hsp27) is a molecular chaperone highly and ubiquitously expressed in aggressive cancers where it controls a variety of pro-tumorigenic signaling pathways. Using gene expression profiling in prostate cancer cells with loss of Hsp27 function, we identified for the first time that Hsp27 regulates target genes in signaling pathways dependent on YAP and TAZ. Suppression of these transcriptional co-activators occurs via their phosphorylation and cytoplasmic retention by the Hippo tumor suppressor pathway. Mechanistic studies revealed that Hsp27 expression is associated with reduced YAP phosphorylation and enhanced transcription of YAP/TAZ target genes. Examination of the core components of the Hippo kinase cascade revealed that Hsp27 facilitates the proteasomal degradation of the core Hippo kinase, MST1, leading to reduced phosphorylation/activity of other main kinases responsible for YAP phosphorylation/inactivation, LATS1 and MOB1. Importantly, our data from cell lines was supported by data from human tumors; clinically, high expression of Hsp27 correlates with increased expression of YAP target genes in prostate cancer as well as reduced phosphorylation of YAP in lung and invasive breast cancer clinical samples. Together, our data reveal a novel mechanism by which Hsp27 regulates the Hippo tumor suppressor pathway, providing further rationale to target Hsp27 in multiple cancers.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat