LncRNA SNORD3A specifically sensitizes breast cancer cells to 5-FU by sponging miR-185-5p to enhance UMPS expression

• Published in: Cell death & disease Vol. 11; no. 5; p. 329
• Main Authors: Luo, Liyun, Zhang, Jianlei, Tang, Hailin, Zhai, Dongfeng, Huang, Danqing, Ling, Li, Wang, Xiaorong, Liu, Ting, Zhang, Qiong, Zhang, Zhijie, He, Zhimin, Zheng, Guopei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.05.2020; Springer Nature B.V
• Subjects: 13/109; 13/95; 5-Fluorouracil; 631/67/1059/99; 631/67/1347; 96/1; Animals; Antibodies; Base Sequence; Biochemistry; Biomedical and Life Sciences; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Biology; Cell Culture; Cell Line, Tumor; Cell proliferation; Chemosensitization; Chemotherapy; Down-Regulation - drug effects; Down-Regulation - genetics; Female; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunology; Life Sciences; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; Multienzyme Complexes - genetics; Multienzyme Complexes - metabolism; Myeloid Ecotropic Viral Integration Site 1 Protein - genetics; Myeloid Ecotropic Viral Integration Site 1 Protein - metabolism; Non-coding RNA; Orotate Phosphoribosyltransferase - genetics; Orotate Phosphoribosyltransferase - metabolism; Orotidine-5'-Phosphate Decarboxylase - genetics; Orotidine-5'-Phosphate Decarboxylase - metabolism; Proteins; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Signal Transduction - drug effects; Therapeutic applications; Transcription; Uridine
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-2557-2

Breast cancer is the most common cancer type in women. Long non-coding RNAs (lncRNAs) have been reported as potential new diagnostic markers, prognostic factors, and therapeutic targets in cancer. However, the specific roles and mechanisms of lncRNAs in breast cancer remain to be elucidated. Here we demonstrated the downregulation of lncRNA SNORD3A in breast cancer cells and tissues and verified its non-protein-coding property. SNORD3A overexpression had no effect on cell proliferation but specifically sensitized breast cancer cells to 5-fluorouracil (5-FU) in vitro and in vivo. Mechanistically, SNORD3A exerts its effect via enhancing uridine monophosphate synthetase (UMPS) protein expression. SNORD3A acts as a competing endogenous RNA for miR-185-5p, leading to UMPS protein upregulation. miR-185-5p overexpression disrupted the effect of SNORD3A on chemosensitization to 5-FU in vitro and in vivo. Moreover, Meis1 overexpression transcriptionally promotes SNORD3A expression, and Meis1 is downregulated in breast cancer cells and tissues. In breast cancer tissues, SNORD3A level positively correlates with Meis1 and UMPS protein levels, whereas miR-185-5p level negatively correlates with UMPS protein level. High SNORD3A transcript and Meis1 and UMPS protein levels predicts a better outcome, but high miR-185-5p level predicts a worse outcome in breast cancer patients receiving 5-FU-based chemotherapy. Our findings indicate that Meis1-regulated SNORD3A specifically sensitizes breast cancer cells to 5-FU via enhancing UMPS expression. The SNORD3A –UMPS axis may serve as a potential biomarker and therapeutic target to improve the efficacy of 5-FU-based chemotherapy for breast cancer patients.