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

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

doi:10.3724/abbs.2023119

Acta Biochimica et Biophysica Sinica (Jun 2023)

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

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

Affiliations

Li Suyao: ["Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Wei Yichou: ["Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Sun Xun: ["Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Liu Mengling: ["Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Zhu Mengxuan: ["Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Yuan Yitao: ["Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Zhang Jiayu: ["Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Dong Yu: ["Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Hu Keshu: ["Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Ma Sining: ["Department of Obstetrics and Gynecology, Zhongshan Hospital, Shanghai 200032, China"]
Zhang Xiuping: ["Department of Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361004, China"]
Xu Bei: ["Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China","Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Jiang Hesheng: ["Department of Surgery, Southwest Healthcare, Southern California Medical Education Consortium, Temecula Valley Hospital, Temecula, CA 92592, USA"]
Gan Lu: ["Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China","Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Liu Tianshu: ["Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China","Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]

DOI: https://doi.org/10.3724/abbs.2023119
Journal volume & issue: Vol. 55
pp. 1784 – 1796

Abstract

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Currently, platinum-containing regimens are the most commonly used regimens for advanced gastric cancer patients, 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 oxaliplatin-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 transcriptional 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 piperlongumine 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.

Published in Acta Biochimica et Biophysica Sinica

ISSN: 1672-9145 (Print); 1745-7270 (Online)
Publisher: China Science Publishing & Media Ltd.
Country of publisher: China
LCC subjects: Science: Chemistry: Organic chemistry: Biochemistry; Science: Biology (General): Genetics
Website: https://www.sciengine.com/ABBS/home

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