Pan-cancer tRNA-derived fragment CAT1 coordinates RBPMS to stabilize NOTCH2 mRNA to promote tumorigenesis

Mengqian Yu; Jiani Yi; Qiongzi Qiu; Dongxia Yao; Jia Li; Juze Yang; Chunyi Mi; Liyuan Zhou; Bingjian Lu; Weiguo Lu; Kejing Ying; Wantao Chen; Enguo Chen; Honghe Zhang; Zhimin Lu; Yan Lu; Pengyuan Liu

doi:10.1016/j.celrep.2023.113408

Pan-cancer tRNA-derived fragment CAT1 coordinates RBPMS to stabilize NOTCH2 mRNA to promote tumorigenesis

Cell Rep. 2023 Nov 28;42(11):113408. doi: 10.1016/j.celrep.2023.113408. Epub 2023 Nov 9.

Authors

Mengqian Yu¹, Jiani Yi², Qiongzi Qiu³, Dongxia Yao³, Jia Li², Juze Yang², Chunyi Mi³, Liyuan Zhou², Bingjian Lu⁴, Weiguo Lu⁴, Kejing Ying⁵, Wantao Chen⁶, Enguo Chen⁵, Honghe Zhang⁷, Zhimin Lu⁸, Yan Lu⁹, Pengyuan Liu¹⁰

Affiliations

¹ Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China; Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China.
² Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China.
³ Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China.
⁴ Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310013, China.
⁵ Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310013, China.
⁶ Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China.
⁷ Department of Pathology, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310013, China.
⁸ Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310013, China. Electronic address: zhiminlu@zju.edu.cn.
⁹ Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310013, China. Electronic address: yanlu76@zju.edu.cn.
¹⁰ Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310013, China; Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85724, USA. Electronic address: pyliu@zju.edu.cn.

PMID: 37943661
DOI: 10.1016/j.celrep.2023.113408

Abstract

Transfer RNA-derived fragments (tRFs) are a class of small non-coding regulatory RNAs that are involved in the pathophysiology of many diseases. However, the role of tRFs in cancer progression remains largely elusive. Here, we demonstrate that a pan-cancer 3'-tRF, CAT1 (cancer associated tRF 1), is ubiquitously upregulated in tumors and associated with poor prognosis of a variety of cancers, including lung cancer. The upregulated CAT1 in cancer cells binds to RNA-binding protein with multiple splicing (RBPMS) and displaces NOTCH2 association from RBPMS, thereby inhibiting the subsequent CCR4-NOT deadenylation-complex-mediated NOTCH2 mRNA decay. The CAT1-enhanced NOTCH2 expression promotes lung cancer cell proliferation and metastasis in vitro and in vivo. In addition, plasma CAT1 levels are substantially increased in patients with lung cancer compared to non-cancer control subjects. Our findings reveal an intrinsic connection between cancer-specific upregulation of CAT1 and cancer progression, show the regulation of NOTCH signaling in cancer by a 3'-tRF, and highlight its great clinical potential.

Keywords: CAT1; CP: Cancer; CP: Molecular biology; NOTCH2; RBPMS; biomarker; gene regulation; mRNA stability; pan-cancer analysis; small noncoding RNA; tRNA-derived fragment; tumorigenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Transformation, Neoplastic
Humans
Lung Neoplasms* / genetics
RNA, Messenger / genetics
RNA, Transfer* / metabolism
RNA-Binding Proteins
Receptor, Notch2 / genetics
Receptor, Notch2 / metabolism

Substances

RNA, Messenger
RNA, Transfer
RNA-Binding Proteins
RBPMS protein, human
NOTCH2 protein, human
Receptor, Notch2