MST1 downregulates TAZ tumor suppressor protein in multiple myeloma and is a potential therapeutic target.

• MST1 expression is high in myeloma cells. • MST1 anticorrelates with transcriptional activator with PDZ-binding motif (TAZ) expression in multiple myeloma cell lines and patient samples. • Inhibition of MST1 upregulates TAZ and its targets. • Pharmacologic or genetic inhibition of MST1 increases cell death in human myeloma cell lines (HMCLs). • Downregulating MST1 sensitizes HMCLs to frontline antimyeloma therapeutics. We have previously reported that transcriptional activator with PDZ-binding motif (TAZ) functions as a tumor suppressor in multiple myeloma (MM). MST1 is a serine-threonine kinase upstream of the Hippo-signaling pathway that functions as a tumor suppressor in many non-hematologic malignancies. However, its role in hematologic malignancies, including MM is still poorly understood. In this article, we provide evidence that MST1 expression is higher in MM and negatively correlates with TAZ expression in both cell lines and patient samples. High MST1 expression was associated with poor clinical outcomes. Genetic or pharmacologic inhibition of MST1 leads to increased TAZ expression and cell death. Importantly, MST1 inhibitors sensitize myeloma cells to frontline antimyeloma agents—lenalidomide and dexamethasone. Taken together, our data reveal a key role for MST1 in MM pathogenesis and provide evidence to explore the therapeutic potential of using MST inhibitors to upregulate TAZ expression in MM to promote response to anticancer agents. [ABSTRACT FROM AUTHOR]