Chang et al. in School of Medicine identified a novel tumor suppressor

A team led by Prof. Zhijie Chang in Tsinghua University and Dr. Y. Eugene Chin in Shanghai Jiaotong University published a paper in the recent issue of Molecular Cell entitled “GdX/UBL4A Specifically Stabilizes the TC45/STAT3 Association and Promotes Dephosphorylation of STAT3 to Repress Tumorigenesis”. This is another striking discovery followed their work on the mechanism of tumorigenesis published on Cancer Cell in 2012.

This study identified an ubiquitin like protein GdX as a novel tumor suppressor. The authors provided crucial insights into the molecular mechanism of the suppression role of GdX in tumor development. Yangmeng Wang, Hongxiu Ning, Fangli Ren and Yuanjiang Zhang contributed equally to this work.

After stimulation of tumor cells by cytokines, STAT3 was activated and induced the expression of tumor related genes, resulting in tumorigenesis. A protein with ubiquin-like domain named GdX specifically bridge a phosphatase called TC45 to STAT3 and induced a process of dephosphorylation of STAT3, finally leading to de-activation of STAT3 and inhibition of tumor growth (Left). When GdX was depleted, tumor cells grow faster significantly (Right upper). The mouse with depletion of GdX demonstrated more colon tumors induced (Right bottom).

This project was in a collaboration with Prof. Yonggong Zhai in Beijing Normal University, Dianjun Wang and Baoqing Jia in Chinese PLA General Hospital, Yasuhiko Tomita in Osaka Medical Center, Joseph JY Sung and Jun Yu in the Chinese University of Hong Kong, David M. Irwin in University of Toronto, Xiao Yang in Institute of Biotechnology and Xinyuan Fu in National University of Singapore also involved in this work.

Regulation of STAT3 signaling has been a hotspot in the field of cancer research. STAT3 is constitutively activated in various kinds of cancers. Phosphatases negatively regulate activated STAT3 directly. It has been a question for the same phosphatase that always targets on different substrates. For instancee, a phosphatase called TC45 dephosphorylates both of STAT1 and STAT3 which play opposite roles in tumor development. Chang’s group reported that GdX determined the specificity of TC45. GdX recruits TC45 specifically to phosphorylated STAT3 and promotes STAT3 dephosphorylation. This work provided a novel mechanism on how a phosphatase targets a specific substrate. Their findings also provide a basis for the development of novel treatment strategies for STAT3-induced cancers.

Chang’s group has worked hard for nearly 10 years on this project. Addition to this project, their recent works were also published on Carcinogenesis, Cellular Signaling and Arthritis & Rheumatology.

This work was supported by grants from the 973 Project, the NSFC and the Tsinghua Science Foundation.