Deubiquitinase YOD1: The potent activator of YAP in hepatomegaly and liver cancer

Advances in the understanding of the Hippo signaling as a keyregulatory pathway of proliferation and apoptosis haveprovided mechanical insights for controlling organ size andtumorigenicity. Recently, much attention has been directed tothe regulation of LATS1/2 (large tumor suppressor) kinases thatphosphorylate YAP/TAZ, a transcriptional co-activator in theHippo pathway, and control the level and nuclear localizationof YAP/TAZ. In our recent work, we showed that deubiquitinaseYOD1 stabilizes ITCH, and facilitates ITCH-mediatedLATS1/2 ubiquitination and degradation, resulting in increasedYAP/TAZ level. Furthermore, we found that the YOD1-ITCH-LATS1/2-YAP/TAZ signaling axis is controlled by thedifferential expression of miR-21 in a cell-density-dependentmanner. Using a transgenic mouse model, we showed that theinducible expression of YOD1 enhances the proliferation ofhepatocytes and leads to hepatomegaly in a YAP/TAZ-activitydependentmanner. Moreover, a strong correlation wasobserved between YOD1 and YAP expression in liver cancerpatients. Overall, our data suggest that YOD1 is a novelregulator of the Hippo pathway, and thereby a potentialtherapeutic target for liver cancer.