N6-methyladenosine-modified TRAF1 promotes sunitinib resistance by regulating apoptosis and angiogenesis in a METTL14-dependent manner in renal cell carcinoma

• DOI: 10.1186/s12943-022-01549-1
• Publication Date: 2022-05-10T06:02:54Z
• Authors: Yuanlei Chen; Zeyi Lu; Chao Qi; Chenhao Yu; Yang Li; Wang Huan; Ruyue Wang; Wenqin Luo; Danyang Shen; Lifeng Ding; Liangliang Ren; Haiyun Xie; Dingwei Xue; Mingchao Wang; Kangxin Ni; Liqun Xia; Jun Qian; Gonghui Li
• Keywords: Male; 0301 basic medicine; Sunitinib-resistance; Adenosine; Angiogenesis Inhibitors; Apoptosis; 03 medical and health sciences; Cell Line, Tumor; Sunitinib; Humans; Carcinoma, Renal Cell; RC254-282; 0303 health sciences; Neovascularization, Pathologic; N6-methyladenosine; Research; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Methyltransferases; RCC; TNF Receptor-Associated Factor 1; Kidney Neoplasms; 3. Good health; TRAF1; Drug Resistance, Neoplasm; METTL14; Female

Abstract Background Sunitinib resistance can be classified into primary and secondary resistance. While accumulating research has indicated several underlying factors contributing to sunitinib resistance, the precise mechanisms in renal cell carcinoma are still unclear. Methods RNA sequencing m6A were used screen for functional genes involved In vitro vivo experiments carried out patient samples clinical information obtained analysis. Results We identified a tumor necrosis factor receptor-associated factor, TRAF1, that was significantly increased sunitinib-resistant cells, resistant cell-derived xenograft (CDX-R) models patients with Silencing TRAF1 sunitinib-induced apoptotic antiangiogenic effects. Mechanistically, upregulated level of cells derived from stability, which caused by an N6-methyladenosine (m6A) METTL14-dependent manner. Moreover, adeno-associated virus 9 (AAV9) -mediated transduction suppressed effects CDX models, whereas knockdown effectively resensitized CDXs treatment. Conclusions Overexpression promotes modulating angiogenic pathways Targeting its may novel pharmaceutical intervention sunitinib-treated patients.