A positive feedback circuit between RN7SK snRNA and m6A readers is essential for tumorigenesis

Xin Xu; Lifang Ma; Xiao Zhang; Susu Guo; Wanxin Guo; Yikun Wang; Shiyu Qiu; Xiaoting Tian; Yayou Miao; Yongchun Yu; Jiayi Wang

doi:10.1016/j.ymthe.2022.12.013

A positive feedback circuit between RN7SK snRNA and m⁶A readers is essential for tumorigenesis

Mol Ther. 2023 Jun 7;31(6):1615-1635. doi: 10.1016/j.ymthe.2022.12.013. Epub 2022 Dec 24.

Authors

Xin Xu¹, Lifang Ma², Xiao Zhang³, Susu Guo², Wanxin Guo³, Yikun Wang², Shiyu Qiu¹, Xiaoting Tian³, Yayou Miao³, Yongchun Yu³, Jiayi Wang⁴

Affiliations

¹ Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241, West Huaihai Rd, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241, West Huaihai Rd, Shanghai 200030, China.
² Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241, West Huaihai Rd, Shanghai 200030, China.
³ Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241, West Huaihai Rd, Shanghai 200030, China.
⁴ Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241, West Huaihai Rd, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241, West Huaihai Rd, Shanghai 200030, China; College of Medical Technology, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin ER Rd, Shanghai 200025, China. Electronic address: Jiayi.wang@sjtu.edu.cn.

PMID: 36566349
PMCID: PMC10277899 (available on 2024-06-07)
DOI: 10.1016/j.ymthe.2022.12.013

Abstract

N⁶-Methyladenosine (m⁶A) RNA modification, methylation at the N6 position of adenosine, plays critical roles in tumorigenesis. m⁶A readers recognize m⁶A modifications and thus act as key executors for the biological consequences of RNA methylation. However, knowledge about the regulatory mechanism(s) of m⁶A readers is extremely limited. In this study, RN7SK was identified as a small nuclear RNA that interacts with m⁶A readers. m⁶A readers recognized and facilitated secondary structure formation of m⁶A-modified RN7SK, which in turn prevented m⁶A reader mRNA degradation from exonucleases. Thus, a positive feedback circuit between RN7SK and m⁶A readers is established in tumor cells. From findings on the interaction with RN7SK, new m⁶A readers, such as EWS RNA binding protein 1 (EWSR1) and KH RNA binding domain containing, signal transduction-associated 1 (KHDRBS1), were identified and shown to boost Wnt/β-catenin signaling and tumorigenesis by suppressing translation of Cullin1 (CUL1). Moreover, several Food and Drug Administration-approved small molecules were demonstrated to reduce RN7SK expression and inhibit tumorigenesis. Together, these findings reveal a common regulatory mechanism of m⁶A readers and indicate that targeting RN7SK has strong potential for tumor treatment.

Keywords: RN7SK; m(6)A methylation; m(6)A readers; regulatory mechanism; tumorigenesis.

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Carcinogenesis* / genetics
Cell Transformation, Neoplastic
DNA-Binding Proteins / metabolism
Feedback
Humans
Methylation
RNA, Small Nuclear* / metabolism
RNA-Binding Proteins / metabolism
Wnt Signaling Pathway

Substances

RNA, Small Nuclear
KHDRBS1 protein, human
DNA-Binding Proteins
RNA-Binding Proteins
Adaptor Proteins, Signal Transducing