The RNF214-TEAD-YAP signaling axis promotes hepatocellular carcinoma progression via TEAD ubiquitylation

RNF214 is an understudied ubiquitin ligase without any knowledge of its biological functions or specific protein substrates. Using an APEX2-mediated proximity labeling method coupled with the mass spectrometry technique, we identified the TEAD transcription factors in the Hippo pathway as the interactors of RNF214. We showed that RNF214 induces non-proteolytic ubiquitylation at a conserved single lysine residue of TEADs, enhances the interactions between TEADs and the transcription coactivators of the Hippo pathway including YAP and TAZ, and then promotes transactivation of the downstream genes of the Hippo signaling. Moreover, we proved that YAP and TAZ could bind polyubiquitin chains, implying the underlying mechanisms by which RNF214 regulates the Hippo pathway. Furthermore, we found that RNF214 is overexpressed in hepatocellular carcinoma (HCC). Clinical and statistical analysis indicated that high expression levels of RNF214 are associated with low differentiation status and poor prognosis of HCC. Consistently, we showcased that RNF214 promotes proliferation, migration and invasion of HCC cells and HCC tumorigenesis in mouse models via the Hippo pathway. Collectively, our data revealed that RNF214 is a critical component in the Hippo pathway by forming a new signaling axis of RNF214-TEAD-YAP, thereby upregulating the transcriptional activities of the YAP/TAZ-TEAD complex. More importantly, our results suggest that RNF214 serves as an oncogene of HCC and could be a potential drug target of HCC therapy.