Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, China.
Acta Pharmacol Sin. 2021 Nov;42(11):1900-1912. doi: 10.1038/s41401-020-00598-w. Epub 2021 Feb 3.
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.
Ras-GTPase 激活 SH3 结构域结合蛋白 1（G3BP1）是一种多功能结合蛋白，参与多种人类癌症的发生。然而，G3BP1 在乳腺癌进展中的作用在很大程度上尚不清楚。在本研究中，我们报告 G3BP1 在乳腺癌中上调，并与预后不良相关。G3BP1 的过表达通过刺激 β-连环蛋白信号通路促进乳腺癌细胞增殖，该信号通路上调了许多与增殖相关的基因。我们进一步表明，G3BP1 通过抑制 β-连环蛋白的泛素蛋白酶体降解而不是影响 β-连环蛋白的转录来提高 β-连环蛋白的稳定性。在机制上，升高的 G3BP1 与 GSK-3β 相互作用并使其失活，从而抑制 β-连环蛋白的磷酸化和降解。扰乱 G3BP1-GSK-3β 相互作用会加速 β-连环蛋白的降解，从而损害乳腺癌细胞的增殖能力。我们的研究表明，G3BP1/GSK-3β/β-连环蛋白轴的调节机制可能是乳腺癌的潜在治疗靶点。
