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PMID: 35538475 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

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

Molecular cancer ·Vol. 21 ·No. 1 ·2022-00-10 ·Pages 111

Chen Y, Lu Z, Qi C, Yu C, Li Y, Huan W, Wang R, Luo W, Shen D, Ding L, Ren L, Xie H, Xue D, Wang M, Ni K, Xia L, Qian J, Li G

Abstract

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. RNA sequencing and m6A sequencing were used to screen for functional genes involved in sunitinib resistance. In vitro and in vivo experiments were carried out and patient samples and clinical information were obtained for clinical analysis. We identified a tumor necrosis factor receptor-associated factor, TRAF1, that was significantly increased in sunitinib-resistant cells, resistant cell-derived xenograft (CDX-R) models and clinical patients with sunitinib resistance. Silencing TRAF1 increased sunitinib-induced apoptotic and antiangiogenic effects. Mechanistically, the upregulated level of TRAF1 in sunitinib-resistant cells was derived from increased TRAF1 RNA stability, which was caused by an increased level of N6-methyladenosine (m6A) in a METTL14-dependent manner. Moreover, in vivo adeno-associated virus 9 (AAV9) -mediated transduction of TRAF1 suppressed the sunitinib-induced apoptotic and antiangiogenic effects in the CDX models, whereas knockdown of TRAF1 effectively resensitized the sunitinib-resistant CDXs to sunitinib treatment. Overexpression of TRAF1 promotes sunitinib resistance by modulating apoptotic and angiogenic pathways in a METTL14-dependent manner. Targeting TRAF1 and its pathways may be a novel pharmaceutical intervention for sunitinib-treated patients.

Keywords
METTL14 N6-methyladenosine RCC Sunitinib-resistance TRAF1
MeSH Terms
Adenosine/analogs & derivatives Angiogenesis Inhibitors/pharmacology Apoptosis/drug effects Carcinoma, Renal Cell/blood supply,drug therapy,genetics,pathology Cell Line, Tumor Drug Resistance, Neoplasm Female Humans Kidney Neoplasms/blood supply,drug therapy,genetics,pathology Male Methyltransferases/metabolism Neovascularization, Pathologic/drug therapy,genetics,metabolism,pathology Sunitinib/pharmacology TNF Receptor-Associated Factor 1/genetics,metabolism
Chemicals
Angiogenesis Inhibitors TNF Receptor-Associated Factor 1 N-methyladenosine METTL14 protein, human Methyltransferases Adenosine Sunitinib
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Chen Yuanlei
Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Qingchun Road, Hangzhou, 310016, China.
Lu Zeyi
Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Qingchun Road, Hangzhou, 310016, China.
Qi Chao
Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China.
Yu Chenhao
Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Qingchun Road, Hangzhou, 310016, China.
Li Yang
Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Qingchun Road, Hangzhou, 310016, China.
Huan Wang
Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Qingchun Road, Hangzhou, 310016, China.
Wang Ruyue
Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Qingchun Road, Hangzhou, 310016, China.
Luo Wenqin
Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Qingchun Road, Hangzhou, 310016, China.
Shen Danyang
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
Ding Lifeng
Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Qingchun Road, Hangzhou, 310016, China.
Ren Liangliang
Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Qingchun Road, Hangzhou, 310016, China.
Xie Haiyun
Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Qingchun Road, Hangzhou, 310016, China.
Xue Dingwei
Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Qingchun Road, Hangzhou, 310016, China.
Wang Mingchao
Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Qingchun Road, Hangzhou, 310016, China.
Ni Kangxin
Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Qingchun Road, Hangzhou, 310016, China.
Xia Liqun
Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Qingchun Road, Hangzhou, 310016, China. xialiqun@zju.edu.cn.
Qian Jun
State Key Laboratory of Modern Optical Instrumentations, Centre for Optical and Electromagnetic Research, College of Optical Science and Engineering, International Research Center for Advanced Photonics, Zhejiang University, Hangzhou, 310058, China. qianjun@zju.edu.cn.
Li Gonghui ORCID
Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Qingchun Road, Hangzhou, 310016, China. 3193119@zju.edu.cn.
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Article Info
Journal
Molecular cancer
Abbr.
Mol Cancer
ISSN
1476-4598
DOI
10.1186/s12943-022-01549-1
Email
xialiqun@zju.edu.cn
qianjun@zju.edu.cn
3193119@zju.edu.cn
Published
2022-00-10
Epub
2022-00-10
Pages
111
Language
English
Region
England
NLM ID
101147698
PMCID
PMC9087993
Subset
IM
External Links
PubMed source DOI: 10.1186/s12943-022-01549-1 PMC Full Text View journal details
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