Ubiquitin Specific peptidase 32 stabilizes YAP and Facilitates Triple Negative Breast Cancer Progression

Triple negative breast cancer (TNBC) is the most lethal among all breast cancer subtypes, while the effective therapeutic targets are still unavailable. Recently studies revealed that the dys-regulation of Hippo signaling played important roles in TNBC progression, but targeting Hippo/YAP axis is a plausible strategy for TNBC therapy. In our study, we carried out GSEA screening for important deubiquitinases (DUBs) for Hippo signaling and identified USP32 as a key mediator for YAP stability and Hippo signaling activity for TNBC progression. USP32 depletion significantly inhibited Hippo/YAP activity and TNBC progression. Molecular mechanism studies showed that USP32 could interact with YAP, enhance YAP stability possibly by inhibiting K63-linked poly-ubiquitination. Interestingly, YAP could also bind to the promoter region of USP32 and facilitate its transcription. In general, our study revealed the positive feedback loop between USP32 and YAP in modulating TNBC progression, while targeting USP32 could be a promising strategy to disrupt such interplay between USP32 and Hippo signaling for TNBC treatment. Overall design: RNA-seq profiling of MDA-MB-231 cells transfected with siControl or siUSP32 for 48h