OTUB2 promotes cancer metastasis via Hippo independent activation of YAP and TAZ, Zhang et al.
The transcriptional regulators YAP and TAZ play important roles in development, physiology and tumorigenesis and are negatively controlled by the Hippo pathway. Upon activation of Hippo signaling, YAP and TAZ are phosphorylated by LATS1/2 and Casein 1δ/ε kinases, leading to poly-ubiquitination by SCF E3 ubiquitin ligase and proteasomal degradation. Although YAP/ TAZ proteins are frequently activated in human malignancies in which the Hippo pathway is still active, it is yet unknown whether YAP/TAZ can be stabilized via deubiquitination and thereby escape from the negative Hippo control. Here, by a gain-of-function cancer metastasis screen we discovered OTUB2 as a cancer stemness and metastasis-promoting factor that deubiquitinates and activates YAP/TAZ. We found OTUB2 to be poly-SUMOylated on Lysine 233 and this SUMOylation enables it to bind YAP/TAZ. We also identified an as yet unknown SUMO-interacting motif (SIM) in YAP and TAZ required for their association with SUMOylated OTUB2. Importantly, EGF and oncogenic KRAS induce OTUB2 poly-SUMOylation and thereby activating YAP/TAZ. Our results not only establish OTUB2 as an essential modulator of YAP/TAZ, but also reveal a novel regulatory mechanism via which YAP/TAZ activity is induced by oncogenic KRAS.