WTAP weakens oxaliplatin chemosensitivity of colorectal cancer by preventing PANoptosis

• Published in: Cancer letters 2024-11, Vol.604, p.217254, Article 217254
• Main Authors: Tan, Yue-Tao, Li, Ting, Wang, Ruo-Bing, Liu, Ze-Kun, Ma, Meng-Yao, Huang, Ren-Ze, Mo, Hai-Yu, Luo, Shu-Yu, Lin, Jin-Fei, Xu, Rui-Hua, Ju, Huai-Qiang
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - pharmacology; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; CRC chemosensitivity; Drug Resistance, Neoplasm - drug effects; Gene Expression Regulation, Neoplastic - drug effects; HCT116 Cells; Humans; m6A modification; Mice; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; NRF2; Oxaliplatin - pharmacology; Oxidative Stress - drug effects; PANoptosis; RNA Splicing Factors - genetics; RNA Splicing Factors - metabolism
• ISSN: 0304-3835; 1872-7980; 1872-7980
• DOI: 10.1016/j.canlet.2024.217254

As the most abundant post-transcriptional modification in eukaryotes, N6-methyladenosine (m6A) plays a crucial role in cancer cell proliferation, invasion and chemoresistance. However, its specific effects on chemosensitivity to oxaliplatin-based regimens and the impact of these drugs on m6A methylation levels in colorectal cancer (CRC) remain largely unexplored. In this study, we demonstrated that the m6A methyltransferase Wilms tumor 1-associating protein (WTAP) weakens oxaliplatin chemosensitivity in HCT116 and DLD1 cells. Mechanistically, oxaliplatin treatment upregulated WTAP expression, preventing multiple forms of cell death simultaneously, a process known as PANoptosis, by decreasing intracellular oxidative stress through maintaining the expression of nuclear factor erythroid-2-related factor 2 (NRF2), a major antioxidant response element, in an m6A-dependent manner. In addition, high WTAP expression in CRC patients is associated with a poor prognosis and reduced benefit from standard chemotherapy by clinical data analysis of The Cancer Genome Atlas (TCGA) database and patient cohort study. These findings suggest that targeting WTAP-NRF2-PANoptosis axis could enhance the antitumor efficacy of oxaliplatin-based chemotherapy in CRC treatment. •Oxaliplatin treatment increases the m6A level in CRC cells.•WTAP depletion triggers PANoptosis with increased ROS to enhance the chemosensitivity.•WTAP stabilizes NRF2 mRNA in an m6A-dependent manner.•High WTAP expression in CRC patients is associated with poor prognosis and reduced benefit from standard chemotherapy.