Identification of BRCC3 and BRCA1 as Regulators of TAZ Stability and Activity
Silvia Sberna,
Alejandro Lopez-Hernandez,
Chiara Biancotto,
Luca Motta,
Adrian Andronache,
Lisette G. G. C. Verhoef,
Marieta Caganova,
Stefano Campaner
Affiliations
Silvia Sberna
Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT), 20139 Milan, Italy
Alejandro Lopez-Hernandez
Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT), 20139 Milan, Italy
Chiara Biancotto
Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT), 20139 Milan, Italy
Luca Motta
Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT), 20139 Milan, Italy
Adrian Andronache
Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT), 20139 Milan, Italy
Lisette G. G. C. Verhoef
Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT), 20139 Milan, Italy
Marieta Caganova
Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT), 20139 Milan, Italy
Stefano Campaner
Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT), 20139 Milan, Italy
TAZ (WWTR1) is a transcriptional co-activator regulated by Hippo signaling, mechano-transduction, and G-protein couple receptors. Once activated, TAZ and its paralogue, YAP1, regulate gene expression programs promoting cell proliferation, survival, and differentiation, thus controlling embryonic development, tissue regeneration, and aging. YAP and TAZ are also frequently activated in tumors, particularly in poorly differentiated and highly aggressive malignancies. Yet, mutations of YAP/TAZ or of their upstream regulators do not fully account for their activation in cancer, raising the possibility that other upstream regulatory pathways, still to be defined, are altered in tumors. In this work, we set out to identify novel regulators of TAZ by means of a siRNA-based screen. We identified 200 genes able to modulate the transcriptional activity of TAZ, with prominence for genes implicated in cell–cell contact, cytoskeletal tension, cell migration, WNT signaling, chromatin remodeling, and interleukins and NF–kappaB signaling. Among these genes we identified was BRCC3, a component of the BRCA1 complex that guards genome integrity and exerts tumor suppressive activity during cancer development. The loss of BRCC3 or BRCA1 leads to an increased level and activity of TAZ. Follow-up studies indicated that the cytoplasmic BRCA1 complex controls the ubiquitination and stability of TAZ. This may suggest that, in tumors, inactivating mutations of BRCA1 may unleash cell transformation by activating the TAZ oncogene.