The novel tumor suppressor IRF2BP2 regulates Hippo pathway

In a recent study published online in Hepatology on September 20, a research group led by Prof. ZHANG Lei at the CAS Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences reported the role of the novel tumor suppressor IRF2BP2 in liver cancer.

HCC is one of the few tumors with high morbidity, high mortality and poor prognosis worldwide. The Hippo pathway, evolutionarily conserved from Drosophila to mammals, precisely controls organ size and tumorigenesis by restricting the oncogenic activity of YAP. However, therapies targeting YAP for the prevention and treatment of HCC remain limited.

IRF2BP2 acts as a transcriptional co-repressor by inhibiting both basal and enhancer-activated transcription, but its exact role and the regulation mechanism of IRF2BP2 in cancers, especially in liver cancer, have not been explored. More importantly, whether IRF2BP2 functions in the Hippo pathway remains largely unknown.

This study reveals the clinical relevance and the feedback regulatory loop between the tumor suppressor IRF2BP2 and the oncogene YAP in HCC. The data show that IRF2BP2 is a novel target gene repressed by the YAP-TEAD transcriptional complex, and exhibits potent antitumor activity by inhibiting YAP activity. The researchers identify that IRF2BP2 interacts with VGLL4 and stabilizes the protein level of VGLL4, which leads to synergistic inhibition toward YAP. Furthermore, liver-specific IRF2BP2 overexpression strongly suppresses liver tumor formation induced by Hippo pathway inactivation. These findings identify a novel IRF2BP2-VGLL4-YAP feedback loop revealing the role and the molecular mechanism of how IRF2BP2 associates with Hippo pathway to regulate liver cancer progression, which may propose a potential strategy for HCC therapy and diagnosis.

FENG Xue, LU Tiantian and their colleagues who are from the research group led by Prof. ZHANG Lei, TIAN Wei and CHENG Shuqun completed this work. The work was financially supported by the National Natural Science Foundation of China, National Key Research and Development Program of China, “Strategic Priority Research Program” of Chinese Academy of Sciences, Shanghai Program, Science and Technology Commission of Shanghai Municipality, Youth Innovation Promotion Association of the Chinese Academy of Sciences and China Postdoctoral Science Foundation.

 

Contact: rayzhang@sibcb.ac.cn.

Reference: https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.30961