SRSF1 modulates PTPMT1 alternative splicing to regulate lung cancer cell radioresistance
| العنوان: | SRSF1 modulates PTPMT1 alternative splicing to regulate lung cancer cell radioresistance |
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| المؤلفون: | Junxiu Sheng, Yuesheng Lv, Yangfan Qi, Lin Zhang, Xiaoling Li, Chundong Gu, Ge Zhang, Hong Gu, Qingzhi Zhao, Lei Chen, Bing Sun, Lu Bai, Judy M. Coulson, Quan Yang, Jinyao Zhao, Wenjing Zhang, Xiaoqin Deng, Yang Wang, Pan Qin, Yu Sun, Songshu Meng, Quentin Liu, Han Liu |
| المصدر: | EBioMedicine |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, AMPK, Lung Neoplasms, Research paper, AMPK, AMP-activated Protein Kinase, PTPMT1, EMT, epithelial to mesenchymal transition, Biology, AMP-Activated Protein Kinases, medicine.disease_cause, Radiation Tolerance, γH2AX, gamma-Histone H2AX, General Biochemistry, Genetics and Molecular Biology, Radio-resistance, 03 medical and health sciences, Splicing factor, Mice, Radioresistance, Cell Line, Tumor, medicine, Animals, Humans, DNA Breaks, Double-Stranded, AS, Alternative Splicing, Serine-Arginine Splicing Factors, NMD, nonsense-mediated decay, PTPMT1, Protein Tyrosine Phosphatase, Mitochondrial 1, Gene Expression Profiling, Chk2, Checkpoint kinase 2, Alternative splicing, PTEN Phosphohydrolase, Cancer, Computational Biology, General Medicine, medicine.disease, Xenograft Model Antitumor Assays, SR proteins, Serine/arginine-rich proteins, Gene Expression Regulation, Neoplastic, SRSF1, Serine/arginine-rich splicing factor 1, Alternative Splicing, Disease Models, Animal, 030104 developmental biology, RNA splicing, Cancer cell, Cancer research, IR, ionizing radiation, SRSF1, Serine/arginine-rich Splicing Factor 1, Carcinogenesis |
| الوصف: | Background Radioresistance is the major cause of cancer treatment failure. Additionally, splicing dysregulation plays critical roles in tumorigenesis. However, the involvement of alternative splicing in resistance of cancer cells to radiotherapy remains elusive. We sought to investigate the key role of the splicing factor SRSF1 in the radioresistance in lung cancer. Methods Lung cancer cell lines, xenograft mice models, and RNA-seq were employed to study the detailed mechanisms of SRSF1 in lung cancer radioresistance. Clinical tumor tissues and TCGA dataset were utilized to determine the expression levels of distinct SRSF1-regulated splicing isoforms. KM-plotter was applied to analyze the survival of cancer patients with various levels of SRSF1-regulated splicing isoforms. Findings Splicing factors were screened to identify their roles in radioresistance, and SRSF1 was found to be involved in radioresistance in cancer cells. The level of SRSF1 is elevated in irradiation treated lung cancer cells, whereas knockdown of SRSF1 sensitizes cancer cells to irradiation. Mechanistically, SRSF1 modulates various cancer-related splicing events, particularly the splicing of PTPMT1, a PTEN-like mitochondrial phosphatase. Reduced SRSF1 favors the production of short isoforms of PTPMT1 upon irradiation, which in turn promotes phosphorylation of AMPK, thereby inducing DNA double-strand break to sensitize cancer cells to irradiation. Additionally, the level of the short isoform of PTPMT1 is decreased in cancer samples, which is correlated to cancer patients' survival. Conclusions Our study provides mechanistic analyses of aberrant splicing in radioresistance in lung cancer cells, and establishes SRSF1 as a potential therapeutic target for sensitization of patients to radiotherapy. Highlights • The splicing factor SRSF1 is identified to regulate cancer cell resistance to IR. • Depleted SRSF1 switches PTPMT1 splicing to sensitize cancer cells to radiation. • PTPMT1 splicing switch induces AMPK phosphorylation to increase radiosensitivity. • PTPMT1B is markedly reduced in cancers, indicating potentials in cancer treatment. |
| وصف الملف: | application/pdf |
| تدمد: | 2352-3964 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cee6b7a92fee63aac22b7f4436470052 https://pubmed.ncbi.nlm.nih.gov/30429088 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....cee6b7a92fee63aac22b7f4436470052 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23523964 |
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