JUNB mediates oxaliplatin resistance via the MAPK signaling pathway in gastric cancer by chromatin accessibility and transcriptomic analysis  

作　　者：Suyao Li Yichou Wei Xun Sun Mengling Liu Mengxuan Zhu Yitao Yuan Jiayu Zhang Yu Dong Keshu Hu Sining Ma Xiuping Zhang Bei Xu Hesheng Jiang Lu Gan Tianshu Liu 

机构地区：[1]Department of Medical Oncology,Zhongshan Hospital,Fudan University,Shanghai 200032,China [2]Cancer Center,Zhongshan Hospital,Fudan University,Shanghai 200032,China [3]Department of Oncology,Zhongshan Hospital(Xiamen),Fudan University,Xiamen 361004,China [4]Department of Obstetrics and Gynecology,Zhongshan Hospital,Shanghai 200032,China [5]Department of Surgery,Southwest Healthcare,Southern California Medical Education Consortium,Temecula Valley Hospital,Temecula,CA 92592,USA

出　　处：《Acta Biochimica et Biophysica Sinica》2023年第11期1784-1796,共13页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from the Foundation of Shanghai Science and Technology Committee (No.19DZ1910102);the Natural Science Foundation of Shanghai (No.23ZR1421300).

摘　　要：tients,and chemotherapy resistance is one of the main reasons for treatment failure.Thus,it is important to reveal the mechanism of oxaliplatin resistance and to seek effective intervention strategies to improve chemotherapy sensitivity,thereby improving the survival and prognosis of gastric cancer patients.To understand the molecular mechanisms of oxaliplatin resistance,we generate an oxaliplatin-resistant gastric cancer cell line and conduct assay for transposase-accessible chromatin sequencing(ATAC-seq)and RNA sequencing(RNA-seq)for both parental and oxaliplatin-resistant AGS cells.A total of 3232 genomic regions are identified to have higher accessibility in ox-aliplatin-resistant cells,and DNA-binding motif analysis identifies JUNB as the core transcription factor in the regulatory network.JUNB is overexpressed in oxaliplatin-resistant gastric cancer cells,and its upregulation is associated with poor prognosis in gastric cancer patients,which is validated by our tissue microarray data.Moreover,chromatin immunoprecipitation sequencing(ChIP-seq)analysis reveals that JUNB binds to the tran-scriptional start site of key genes involved in the MAPK signaling pathway.Knockdown of JUNB inhibits the MAPK signaling pathway and restores sensitivity to oxaliplatin.Combined treatment with the ERK inhibitor piperlongu-mine or MEK inhibitor trametinib effectively overcomes oxaliplatin resistance.This study provides evidence that JUNB mediates oxaliplatin resistance in gastric cancer by activating the MAPK pathway.The combination of MAPK inhibitors with oxaliplatin overcomes resistance to oxaliplatin,providing a promising treatment opportunity for oxaliplatin-resistant gastric cancer patients.

关 键 词：gastric cancer JUNB ATAC-seq oxaliplatin resistance MAPK signaling pathway chromatin accessibility 

分 类 号：R730[医药卫生—肿瘤]