USP1 Regulates TAZ Protein Stability Through Ubiquitin Modifications in Breast Cancer

SIMPLE SUMMARY: Triple-Negative breast cancer (TNBC) is the most aggressive form of breast cancer in women. Targeted therapies for the treatment of this disease are severely lacking. Through mechanistic studies of the key component of Hippo signaling pathway, Transcriptional co-activator with PDZ-binding motif (TAZ), we aimed to uncover novel regulators that may be used as targeted therapies for this disease. Using an siRNA target deubiquitinating enzymes screen, we identified ubiquitin-specific peptidase 1 (USP1) as a novel TAZ deubiquitinating enzyme. We found that USP1 interacts with TAZ and loss of USP1 reduces cell proliferation in a partially TAZ-dependent manner. Furthermore, we demonstrated that USP1 and TAZ expression are positively correlated in TNBC patients. This research found a newly defined regulatory mechanism of TAZ that could be used as a therapeutic approach for breast cancer. ABSTRACT: The Hippo signaling pathway is an evolutionarily conserved pathway that was initially discovered in Drosophila melanogaster and was later found to have mammalian orthologues. The key effector proteins in this pathway, YAP/TAZ, are often dysregulated in cancer, leading to a high degree of cell proliferation, migration, metastasis and cancer stem cell populations. Due to these malignant phenotypes it is important to understand the regulation of YAP/TAZ at the protein level. Using an siRNA library screen of deubiquitinating enzymes (DUBs), we identified ubiquitin specific peptidase 1 (USP1) as a novel TAZ (WWTR1) regulator. We demonstrated that USP1 interacts with TAZ and increases TAZ protein stability. Conversely, loss of function of USP1 reduces TAZ protein levels through increased poly-ubiquitination, causing a decrease in cell proliferation and migration of breast cancer cells. Moreover, we showed a strong positive correlation between USP1 and TAZ in breast cancer patients. Our findings facilitate the attainment of better understanding of the crosstalk between these pathways and may lead to potential therapeutic interventions for breast cancer patients.