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

Zhuojia Chen; Long Wu; Jiawang Zhou; Xinyao Lin; Yanxi Peng; Lichen Ge; Cheng-Ming Chiang; Hui Huang; Hongsheng Wang; Weiling He

doi:10.7150/thno.40144

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

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

Authors

Zhuojia Chen¹, Long Wu^{2

3}, Jiawang Zhou², Xinyao Lin², Yanxi Peng², Lichen Ge^{2

4}, Cheng-Ming Chiang⁵, Hui Huang⁶, Hongsheng Wang², Weiling He⁷

Affiliations

¹ Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
² Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, 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.

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: CPT1B; ABCB1; Chemoresistance; ERRγ; FAO.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / genetics
ATP Binding Cassette Transporter, Subfamily B / metabolism
Adenosine / analogs & derivatives*
Adenosine / pharmacology
Animals
Cell Line, Tumor
Drug Delivery Systems
Drug Resistance, Multiple
Drug Resistance, Neoplasm* / drug effects
Fatty Acids / metabolism
Gene Expression Regulation, Neoplastic
Hep G2 Cells
Humans
MCF-7 Cells
Mice
Receptors, Estrogen / metabolism*
Up-Regulation

Substances

ABCB1 protein, human
ATP Binding Cassette Transporter, Subfamily B
ESRRG protein, human
Fatty Acids
Receptors, Estrogen
N-methyladenosine
Adenosine

Abstract

Publication types

MeSH terms

Substances

Grants and funding