GSK3b-mediated expression of CUG-translated WT1 is critical for tumor progression

Hisae Yoshitomi, Kun Y. Lee, Ke Yao, Seung Ho Shin, Tianshun Zhang, Qiushi Wang, Souren Paul, Eunmiri Roh, Joohyun Ryu, Hanyong Chen, Faisal Aziz, Abhijit Chakraborty, Ann M. Bode, Zigang Dong

Research output: Contribution to journalArticlepeer-review

Abstract

The Wilms’ tumor 1 (WT1) gene is well known as a chameleon gene. It plays a role as a tumor suppressor in Wilms’ tumor but also acts as an oncogene in other cancers. Previously, our group reported that a canonical AUG starting site for the WT1 protein (augWT1) acts as a tumor suppressor, whereas a CUG starting site for the WT1 protein (cugWT1) functions as an oncogene. In this study, we report an oncogenic role of cugWT1 in the AOM/DSS-induced colon cancer mouse model and in a urethane-induced lung cancer model in mice lacking cugWT1. Development of chemically-induced tumors was significantly depressed in cugWT1-deficient mice. Moreover, glycogen synthase kinase 3b promoted phosphorylation of cugWT1 at S64, resulting in ubiquitination and degradation of the cugWT1 associated with the F-box-/- WD repeat-containing protein 8. Overall, our findings suggest that inhibition of cugWT1 expression provides a potential candidate target for therapy. Significance: These findings demonstrate that CUG-translated WT1 plays an oncogenic role in vivo, and GSK3b-mediated phosphorylation of cugWT1 induces its ubiquitination and degradation in concert with FBXW8.

Original languageEnglish (US)
Pages (from-to)945-955
Number of pages11
JournalCancer Research
Volume81
Issue number4
DOIs
StatePublished - Feb 15 2021

Bibliographical note

Publisher Copyright:
© 2020 American Association for Cancer Research.

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