Feng Xinhua's team revealed the role and molecular mechanism of HERC3 in promoting YAP/TAZ protein stability and tumorigenesis and development

Cell signaling controls every link
of cell structure and function, tissue differentiation and organ development, and individual physiological function.
Cells and even the body sense and adapt to environmental changes by regulating the cell signal transduction network, and the disorder of cell signal transduction plays an important role
in cell growth disorder and tumorigenesis and development.
Overactivation of the transcriptional coactivator YAP/TAZ in the Hippo signaling pathway plays a key role
in tumorigenesis.
Abnormal activation of YAP/TAZ unrelated to Hippo signaling has also been observed in human malignancies, but the mechanism remains largely unclear
.

Recently, the Feng Xinhua team of the Institute of Life Sciences of Zhejiang University and the team of Zhao Bin published a research paper
entitled: HERC3 promotes YAP/TAZ stability and tumorigenesis independently of its ubiquitin ligase activity in The EMBO Journal.

The study showed that the ubiquitin ligase HERC3 does not rely on its catalytic activity to antagonize the function of another ubiquitin ligase, SCFβ-TrCP, improve the stability of YAP/TAZ protein, and then promote the development
of breast cancer tumors.

In this study, it was found for the first time that the stability and activation of the YAP/TAZ protein can be regulated by the ubiquitin ligase HERC3 and does not depend on the catalytic activity
of the ubiquitin ligase.
The reduction of HERC3 leads to a decrease in YAP/TAZ at the protein level and a decrease
in downstream target gene expression.

Mechanistic studies have shown that HERC3 binds to the substrate recognition subunit of ubiquitin ligase b-TrCP, subsequently blocks the recruitment of substrate YAP/TAZ by b-TrCP, and antagonizes SCFβ-TrCP-mediated ubiquitination of YAP/TAZ protein and proteasome degradation
.
Further experiments found that the deletion of HERC3 inhibited the proliferation and metastasis of breast cancer cells, which could be reversed by YAP/TAZ activation mutations, confirming that HERC3 promoted the occurrence and development
of breast tumors by enhancing YAP/TAZ function.
In addition, HERC3 was highly expressed in breast cancer patient samples, and its higher expression was positively correlated with YAP/TAZ protein levels and negatively correlated
with patient survival.
The above research not only revealed a new mechanism for regulating YAP/AZ, but also elucidated a new mechanism
of action for HERC3.

The role and molecular mechanism of HERC3 in promoting YAP/TAZ protein stability and tumorigenesis and its molecular mechanism

Yuan Bo, a young researcher in Feng Xinhua Laboratory, Liu Jinquan, a postdoctoral fellow (currently working in the First Affiliated Hospital of Zhejiang University), and Shi Aiping, a professor at Bethune Hospital affiliated to Jilin University, are co-first authors of the paper, and Feng Xinhua and Zhao Bin are co-corresponding authors
.
This work was supported by the National Natural Science Foundation of China Key Project, Major Research Program Key Support Project, Regional Innovation and Development Joint Fund, Zhejiang Provincial Natural Science Foundation Major Project, China Postdoctoral Science Foundation and Central University Basic Research Fund
.