Theranostics 2020; 10(8):3382-3396. doi:10.7150/thno.40144

Research Paper

N6-methyladenosine-induced ERRγ triggers chemoresistance of cancer cells through upregulation of ABCB1 and metabolic reprogramming

Zhuojia Chen2#, Long Wu1,3#, Jiawang Zhou1#, Xinyao Lin1#, Yanxi Peng1, Lichen Ge1,4, Cheng-Ming Chiang5, Hui Huang6, Hongsheng Wang1✉, Weiling He7✉

1. Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China
2. Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
3. Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
4. Department of Clinical Laboratory, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, China
5. Simmons Comprehensive Cancer Center, Department of Pharmacology, and Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA
6. Cardiovascular Department, The Eighth Affiliated Hospital, Sun Yat-sen University, Shennan Middle Road 3025#, Shenzhen, 518033, China
7. Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
# These authors contributed equally to this work.

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Citation:
Chen Z, Wu L, Zhou J, Lin X, Peng Y, Ge L, Chiang CM, Huang H, Wang H, He W. N6-methyladenosine-induced ERRγ triggers chemoresistance of cancer cells through upregulation of ABCB1 and metabolic reprogramming. Theranostics 2020; 10(8):3382-3396. doi:10.7150/thno.40144. Available from http://www.thno.org/v10p3382.htm

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Abstract

Background: Drug resistance severely reduces treatment efficiency of chemotherapy and leads to poor prognosis. However, regulatory factors of chemoresistant cancer cells are largely unknown.

Methods: The expression of estrogen receptor related receptors (ERRs) in chemoresistant cancer cells are checked. The roles of ERRγ in chemoresistance are confirmed by in vitro and in vivo studies. The mechanisms responsible for ERRγ-regulated expression of ABCB1 and CPT1B are investigated.

Results: The expression of ERRγ is upregulated in chemoresistant cancer cells. Targeted inhibition of ERRγ restores the chemosensitivity. ERRγ can directly bind to the promoter of ABCB1 to increase its transcription. An elevated interaction between ERRγ and p65 in chemoresistant cells further strengthens transcription of ABCB1. Further, ERRγ can increase the fatty acid oxidation (FAO) in chemoresistant cells via regulation of CPT1B, the rate-limiting enzyme of FAO. The upregulated ERRγ in chemoresistant cancer cells might be due to increased levels of N6-methyladenosine (m6A) can trigger the splicing of precursor ESRRG mRNA.

Conclusions: m6A induced ERRγ confers chemoresistance of cancer cells through upregulation of ABCB1 and CPT1B.

Keywords: Chemoresistance, ERRγ, ABCB1, CPT1B, FAO