G3BP1 promotes human breast cancer cell proliferation through coordinating with GSK-3β and stabilizing β-catenin

• Published in: Acta pharmacologica Sinica 2021-11, Vol.42 (11), p.1900-1912
• Main Authors: Zhang, Cong-hui, Liu, Hong, Zhao, Wu-li, Zhao, Wen-xia, Zhou, Hui-min, Shao, Rong-guang
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin - antagonists & inhibitors; beta Catenin - metabolism; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - physiology; Degradation; DNA Helicases - biosynthesis; Female; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta - metabolism; Humans; Immunology; Internal Medicine; MCF-7 Cells; Medical Microbiology; Mice; Mice, Inbred BALB C; Mice, Nude; Pharmacology/Toxicology; Phosphorylation; Poly-ADP-Ribose Binding Proteins - biosynthesis; Proteasomes; RNA Helicases - biosynthesis; RNA Recognition Motif Proteins - biosynthesis; Transcription; Ubiquitin; Vaccine; Xenograft Model Antitumor Assays - methods; β-Catenin
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-020-00598-w

Ras-GTPase activating SH3 domain-binding protein 1 (G3BP1) is a multifunctional binding protein involved in the development of a variety of human cancers. However, the role of G3BP1 in breast cancer progression remains largely unknown. In this study, we report that G3BP1 is upregulated and correlated with poor prognosis in breast cancer. Overexpression of G3BP1 promotes breast cancer cell proliferation by stimulating β-catenin signaling, which upregulates a number of proliferation-related genes. We further show that G3BP1 improves the stability of β-catenin by inhibiting its ubiquitin-proteasome degradation rather than affecting the transcription of β-catenin. Mechanistically, elevated G3BP1 interacts with and inactivates GSK-3β to suppress β-catenin phosphorylation and degradation. Disturbing the G3BP1-GSK-3β interaction accelerates the degradation of β-catenin, impairing the proliferative capacity of breast cancer cells. Our study demonstrates that the regulatory mechanism of the G3BP1/GSK-3β/β-catenin axis may be a potential therapeutic target for breast cancer.