HERC3 promotes YAP/TAZ stability and tumorigenesis independently of its ubiquitin ligase activity

YAP/TAZ transcriptional co‐activators play pivotal roles in tumorigenesis. In the Hippo pathway, diverse signals activate the MST‐LATS kinase cascade that leads to YAP/TAZ phosphorylation, and subsequent ubiquitination and proteasomal degradation by SCF β‐TrCP . When the MST‐LATS kinase cascade is inactive, unphosphorylated or dephosphorylated YAP/TAZ translocate into the nucleus to mediate TEAD‐dependent gene transcription. Hippo signaling‐independent YAP/TAZ activation in human malignancies has also been observed, yet the mechanism remains largely elusive. Here, we report that the ubiquitin E3 ligase HERC3 can promote YAP/TAZ activation independently of its enzymatic activity. HERC3 directly binds to β‐TrCP, blocks its interaction with YAP/TAZ, and thus prevents YAP/TAZ ubiquitination and degradation. Expression levels of HERC3 correlate with YAP/TAZ protein levels and expression of YAP/TAZ target genes in breast tumor cells and tissues. Accordingly, knockdown of HERC3 expression ameliorates tumorigenesis of breast cancer cells. Our results establish HERC3 as a critical regulator of the YAP/TAZ stability and a potential therapeutic target for breast cancer. Synopsis The activity of the Hippo pathway transcriptional co‐activators YAP/TAZ is regulated by several ubiquitin E3 ligases, including the SCF β‐TrCP complex. This study identifies a non‐enzymatic role of the E3 ligase HERC3 in regulation of YAP/TAZ stability in breast cancer. HERC3 can promote YAP/TAZ activation independently of its catalytic activity. HERC3 directly binds to the β‐TrCP substrate recognition subunit to block its recruitment to YAP/TAZ, thus preventing YAP/TAZ ubiquitination and degradation. HERC3 promotes breast tumorigenesis in a YAP/TAZ‐dependent manner. HERC3 expression level correlates with that of YAP/TAZ and their target genes in breast cancer. Graphical Abstract Degradation of two Hippo pathway effectors via the SCF β‐TrCP ubiquitin ligase complex is unexpectedly prevented by another E3 ligase blocking their interaction.