RT Journal Article SR Electronic T1 Division of labor between YAP and TAZ in non-small cell lung cancer JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.01.12.894733 DO 10.1101/2020.01.12.894733 A1 Michal Shreberk-Shaked A1 Bareket Dassa A1 Sanju Sinha A1 Silvia Di Agostino A1 Ido Azuri A1 Yael Aylon A1 Giovanni Blandino A1 Eytan Ruppin A1 Moshe Oren YR 2020 UL http://biorxiv.org/content/early/2020/01/14/2020.01.12.894733.abstract AB Lung cancer is the leading cause of cancer-related deaths worldwide. The paralogous transcriptional cofactors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ, also called WWTR1), the main downstream effectors of the Hippo signal transduction pathway, are emerging as pivotal determinants of malignancy in lung cancer. Traditionally, studies have tended to consider YAP and TAZ as functionally redundant transcriptional cofactors, with similar biological impact. However, there is growing evidence that each of them also possesses distinct attributes. Here, we sought to systematically characterize the division of labor between YAP and TAZ in non-small cell lung cancer (NSCLC), the most common histological subtype of lung cancer. Employing representative NSCLC cell lines, as well as patient-derived data, we show that the two paralogs orchestrate non-overlapping transcription programs in this cancer type: whereas YAP preferentially regulates gene sets associated with cell division and cell cycle progression, TAZ preferentially regulates genes associated with extracellular matrix organization. Concordantly, depletion of YAP, but not TAZ, leads to growth arrest, while YAP overexpression promotes cell proliferation. Likewise, depletion of TAZ, but not YAP, compromises cell migration, whereas TAZ overexpression enhances migration. Importantly, the differential effects of YAP vs TAZ on key cellular processes are also associated with differential response to anti-cancer therapies. Uncovering the different activities and downstream effects of YAP and TAZ may thus facilitate better stratification of lung cancer patients for anti-cancer therapies.