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

• Published in: Cell reports (Cambridge) Vol. 42; no. 11; p. 113408
• Main Authors: Yu, Mengqian, Yi, Jiani, Qiu, Qiongzi, Yao, Dongxia, Li, Jia, Yang, Juze, Mi, Chunyi, Zhou, Liyuan, Lu, Bingjian, Lu, Weiguo, Ying, Kejing, Chen, Wantao, Chen, Enguo, Zhang, Honghe, Lu, Zhimin, Lu, Yan, Liu, Pengyuan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.11.2023; Elsevier
• Subjects: biomarker; CAT1; Cell Transformation, Neoplastic; CP: Cancer; CP: Molecular biology; gene regulation; Humans; Lung Neoplasms - genetics; mRNA stability; NOTCH2; pan-cancer analysis; RBPMS; Receptor, Notch2 - genetics; Receptor, Notch2 - metabolism; RNA, Messenger - genetics; RNA, Transfer - metabolism; RNA-Binding Proteins; small noncoding RNA; tRNA-derived fragment; tumorigenesis; NOTCH2; CAT1; RBPMS; small noncoding RNA; gene regulation; CP: Cancer; CP: Molecular biology; tumorigenesis; biomarker; pan-cancer analysis; tRNA-derived fragment; mRNA stability
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113408

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. [Display omitted] •CAT1 is upregulated and associated with poor prognosis in many types of cancer•Upregulated CAT1 in lung cancer cells displaces NOTCH2 bound to RBPMS•Displacement of CAT1 inhibits RBPMS/CCR4-NOT-mediated decay of NOTCH2 mRNA•CAT1 promotes lung carcinogenesis through regulation of NOTCH signaling Yu et al. show that a pan-cancer 3′-tRF, CAT1, is upregulated in many human cancers and associated with poor prognosis and discovered that CAT1 interacts with RBPMS to regulate NOTCH signaling in cancer cells. These findings suggest that targeting CAT1 could be a promising strategy for non-invasive cancer diagnosis and therapy.