癌症研究
MAPK/ERK通路
细胞生长
化学
基因敲除
顺铂
细胞凋亡
下调和上调
细胞周期
染色质免疫沉淀
细胞生物学
生物
信号转导
生物化学
基因表达
化疗
基因
发起人
遗传学
作者
Jing Wu,Zhijun Zhou,Jin Li,Huifang Liu,Huaqi Zhang,Junchang Zhang,Wanzhi Huang,Yulong He,Shiyu Zhu,Mingyu Huo,Mingyang Li,Changhua Zhang
标识
DOI:10.1016/j.drup.2022.100913
摘要
Chemoresistance remains a major challenge in gastric cancer (GC). Chromodomain helicase DNA-binding protein 4 (CHD4) mediated chromatin remodeling plays critical roles in various tumor types, but its role in chemoresistance in GC remains uncharacterized.CHD4 expression was examined by immunohistochemistry and Western blotting. The role of CHD4 on cell proliferation and chemoresistance of GC was examined in vitro and in vivo. Immunoprecipitation and liquid chromatography-mass spectrometry were used to identify CHD4-binding proteins and a proximity ligation assay was used to explore protein-protein interaction.Chemoresistance is associated with upregulation of CHD4 in the tumor tissues of GC patients. Overexpression of CHD4 increased chemoresistance and cell proliferation. Knockdown of CHD4 induced cell apoptosis and cell cycle arrest. CHD4 mediates the decrease of the intracellular concentration of cisplatin by inducing drug efflux. Additionally, CHD4 promotes the interaction between ERK1/2 and MEK1/2, resulting in continuous activation of MEK/ERK pathway. Knockdown of CHD4 in GC increased sensitivity to chemotherapy and suppressed tumor growth in a mouse xenograft model.This study identifies CHD4 dominated multi-drug efflux as a promising therapeutic target for overcoming acquired chemoresistance in GC.
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