1. RNA-binding protein NONO contributes to cancer cell growth and confers drug resistance as a theranostic target in TNBC
- Author
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Chan-Gi Pack, Kum Kum Khanna, Prahlad V. Raninga, Seong-il Eyun, Gordon B. Mills, Young Ha Kim, Balázs Győrffy, Seong-Jin Kim, Myoung-Hee Kang, Hee Dong Han, Yun Yong Park, Jin Sung Ju, Hee Jin Lee, Yong Shin, Ji Won Eun, and Gyungyub Gong
- Subjects
STAT3 Transcription Factor ,0301 basic medicine ,Medicine (miscellaneous) ,Apoptosis ,Triple Negative Breast Neoplasms ,RNA-binding protein ,Biology ,Theranostic Nanomedicine ,STAT3 ,03 medical and health sciences ,0302 clinical medicine ,RBP ,Cell Movement ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Gene expression ,Humans ,Precision Medicine ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Cell Proliferation ,Drug Carriers ,Messenger RNA ,Cell growth ,RNA-Binding Proteins ,RNA ,Genomics ,Phenotype ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,biology.protein ,Nanoparticles ,Female ,Drug Screening Assays, Antitumor ,Auranofin ,NONO ,TNBC ,Signal Transduction ,Research Paper - Abstract
Breast cancer (BC) is one of the most common cancers in women. TNBC (Triple-negative breast cancer) has limited treatment options and still lacks viable molecular targets, leading to poor outcomes. Recently, RNA-binding proteins (RBPs) have been shown to play crucial roles in human cancers, including BC, by modulating a number of oncogenic phenotypes. This suggests that RBPs represent potential molecular targets for BC therapy. Methods: We employed genomic data to identify RBPs specifically expressed in TNBC. NONO was silenced in TNBC cell lines to examine cell growth, colony formation, invasion, and migration. Gene expression profiles in NONO-silenced cells were generated and analyzed. A high-throughput screening for NONO-targeted drugs was performed using an FDA-approved library. Results: We found that the NONO RBP is highly expressed in TNBC and is associated with poor patient outcomes. NONO binds to STAT3 mRNA, increasing STAT3 mRNA levels in TNBC. Surprisingly, NONO directly interacts with STAT3 protein increasing its stability and transcriptional activity, thus contributing to its oncogenic function. Importantly, high-throughput drug screening revealed that auranofin is a potential NONO inhibitor and inhibits cell growth in TNBC. Conclusions: NONO is an RBP upstream regulator of both STAT3 RNA and protein levels and function. It represents an important and clinically relevant promoter of growth and resistance of TNBCs. NONO is also therefore a potential therapeutic target in TNBC.
- Published
- 2020