GSG2 promotes aerobic glycolysis and colorectal cancer progression via the MDM2-p53 axis.
TL;DR
The findings reveal a novel way that p53 is silenced in cancers with wild-type TP53, and control of the MDM2-p53 axis to promote the Warburg effect and drive CRC progression via p53 suppression is demonstrated.
Abstract
Colorectal cancer (CRC) is the third most common type of cancer worldwide and ranks among the leading causes of cancer-related deaths. During tumor progression, post-translational modifications, mainly the ubiquitin-proteasome system, are critical mediators of cellular metabolic reprogramming, including the metabolic changes of tumor development. Although TP53 mutations occur in approximately half of all CRC cases and could define their genetic makeup, precise therapeutic vulnerabilities remain largely unknown for the subgroup with wild-type p53. This study investigated the significant expression of Germ Cell-Specific Gene 2 (GSG2) in CRC. We demonstrated GSG2 is strongly increased in malignant colorectal tissues compared with adjacent benign tissues, and this high expression strongly predicts poor patient survival. Additionally, the results indicate that removing GSG2 effectively suppresses tumor growth in both in vitro systems and in vivo xenograft models. Mechanistically, GSG2 directly binds to the E3 ligase MDM2, and promoted MDM2-mediated ubiquitination and degradation of p53 in p53 wild-type CRC cells. Consequently, GSG2 enhances the cellular metabolic program, reprogramming glucose use toward aerobic glycolysis to meet the energy needs of uncontrolled growth. Thus, our findings reveal a novel way that p53 is silenced in cancers with wild-type TP53. GSG2 demonstrate control of the MDM2-p53 axis to promote the Warburg effect and drive CRC progression via p53 suppression.