Affiliation:
1. Sun Yat‐sen University Cancer Center the State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Center for Precision Medicine of Sun Yat‐sen University Guangzhou 510060 P. R. China
2. Department of Radiation Oncology Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China
3. Department of Experimental Research Sun Yat‐sen University Cancer Center Guangzhou 510060 P. R. China
Abstract
AbstractSenescence is associated with tumor metastasis and chemotherapy resistance, yet the mechanisms remain elusive. Here, it is identified that nasopharyngeal carcinoma (NPC) patients who developed distant metastasis are characterized by senescence phenotypes, in which circWDR37 is a key regulator. CircWDR37 deficiency limits cisplatin or gemcitabine‐induced senescent NPC cells from proliferation, migration, and invasion. Mechanistically, circWDR37 binds to and dimerizes double‐stranded RNA‐activated protein kinase R (PKR) to initiate PKR autophosphorylation and activation. Independent of its kinase activity, phosphorylated PKR induces I‐kappaB kinase beta (IKKβ) phosphorylation, binds to and releases RELA from NF‐κB inhibitor alpha (IκBα) to trigger nuclear factor kappa B (NF‐κB) activation, thereby stimulating cyclin D1 (CCND1) and senescence‐associated secretory phenotype component gene transcription in a circWDR37‐dependent manner. Low circWDR37 levels correlate with chemotherapy response and favorable survival in NPC patients treated with gemcitabine or cisplatin induction chemotherapy. This study uncovers a new mechanism of circWDR37 activated PKR in senescence‐driven metastasis and provides appealing therapeutic targets in NPC.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Guangdong Province
Overseas Expertise Introduction Project for Discipline Innovation
Higher Education Discipline Innovation Project
Subject
General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)
Cited by
6 articles.
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