G3BP1 interacts with YWHAZ to regulate chemoresistance and predict adjuvant chemotherapy benefit in gastric cancer

• DOI: 10.1038/s41416-020-01067-1
• Publication Date: 2020-09-29T01:02:33Z
• Authors: Junjie Zhao; Xuhong Fu; Hao Chen; Lingqiang Min; Jie Sun; Jingyi Yin; Jianping Guo; Haojie Li; Zhaoqing Tang; Yuanyuan Ruan; Xuefei Wang; Yihong Sun; Liyu Huang
• Keywords: 0301 basic medicine; DNA Helicases; Article; 3. Good health; Mice; 03 medical and health sciences; RNA Recognition Motif Proteins; 14-3-3 Proteins; Chemotherapy, Adjuvant; Drug Resistance, Neoplasm; Stomach Neoplasms; Biomarkers, Tumor; Animals; Heterografts; Humans; Poly-ADP-Ribose Binding Proteins; RNA Helicases

AbstractBACKGROUNDA large proportion of gastric cancer patients are susceptible to chemoresistance, while the underlying mechanism remains obscure. Stress granules (SGs) play a self-defence role for tumour cells in inhibiting chemotherapy-induced apoptosis. As an SG assembly effector, G3BP1 (Ras-GTPase-activating protein SH3 domain-binding protein) has been reported to be overexpressed in gastric cancer; thus, here we aim to explore its potent roles in gastric cancer chemoresistance.METHODSKaplan–Meier analysis was used to compare survival rates in gastric cancer patients with different G3BP1 expression. The influence of G3BP1 on gastric cancer cell chemoresistance and apoptosis were evaluated by in vitro and in vivo approaches. The interaction between G3BP1 and YWHAZ was assessed by immunohistochemistry, immunoprecipitation and immunofluorescence.RESULTSG3BP1 was associated with the poor outcome of gastric cancer patients who received adjuvant chemotherapy.G3BP1knockdown significantly increased the sensitivity of gastric cancer cells to chemotherapy drugs. Mechanically, cell apoptosis and pro-apoptotic-associated molecules were significantly elevated uponG3BP1depletion. Gene co-expression network analyses identified YWHAZ as the critical interlayer of G3BP1; as a result, G3BP1 interacted with YWHAZ to sequester Bax into the cytoplasm. Clinically, G3BP1highYWHAZhighgastric cancer patients displayed the worst outcome compared with other patients after chemotherapy.CONCLUSIONSThe expression of G3BP1 and YWHAZ could predict the adjuvant chemotherapy benefit in gastric cancer patients.