Splicing factors control triple-negative breast cancer cell mitosis through SUN2 interaction and sororin intron retention
| Autor: | Eline van Steijn, Esmee Koedoot, Marjolein Vermeer, Alfred C.O. Vertegaal, Román González-Prieto, John W.M. Martens, Bob van de Water, Sylvia E. Le Dévédec |
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| Přispěvatelé: | Medical Oncology |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
RNA Splicing Factors Cancer Research RNA splicing Cell Proliferation Mitosis Triple Negative Breast Neoplasms Biology Transfection lcsh:RC254-282 Splicing factors 03 medical and health sciences Splicing factor Mice 0302 clinical medicine SDG 3 - Good Health and Well-being Triple-negative breast cancer Cell Line Tumor Sister chromatid cohesion medicine Animals Humans Cell Proliferation Research Intron Intracellular Signaling Peptides and Proteins RNA Membrane Proteins lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Introns Establishment of sister chromatid cohesion 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer research Female |
| Zdroj: | Journal of Experimental & Clinical Cancer Research, 40. Springer Science and Business Media LLC Journal of Experimental and Clinical Cancer Research, 40(1). BMC Journal of Experimental & Clinical Cancer Research, 40(1):82. BioMed Central Ltd. Journal of Experimental & Clinical Cancer Research : CR Journal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-17 (2021) |
| ISSN: | 0392-9078 |
| Popis: | Background Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic opportunities. Recently, splicing factors have gained attention as potential targets for cancer treatment. Here we systematically evaluated the role of RNA splicing factors in TNBC cell proliferation. Methods In this study, we performed an RNAi screen targeting 244 individual splicing factors to systematically evaluate their role in TNBC cell proliferation. For top candidates, mechanistic insight was gained using amongst others western blot, PCR, FACS, molecular imaging and cloning. Pulldown followed by mass spectrometry were used to determine protein-protein interactions and patient-derived RNA sequencing data was used relate splicing factor expression levels to proliferation markers. Results We identified nine splicing factors, including SNRPD2, SNRPD3 and NHP2L1, of which depletion inhibited proliferation in two TNBC cell lines by deregulation of sister chromatid cohesion (SCC) via increased sororin intron 1 retention and down-regulation of SMC1, MAU2 and ESPL1. Protein-protein interaction analysis of SNRPD2, SNRPD3 and NHP2L1 identified that seven out of the nine identified splicing factors belong to the same spliceosome complex including novel component SUN2 that was also critical for efficient sororin splicing. Finally, sororin transcript levels are highly correlated to various proliferation markers in BC patients. Conclusion We systematically determined splicing factors that control proliferation of breast cancer cells through a mechanism that involves effective sororin splicing and thereby appropriate sister chromatid cohesion. Moreover, we identified SUN2 as an important new spliceosome complex interacting protein that is critical in this process. We anticipate that deregulating sororin levels through targeting of the relevant splicing factors might be a potential strategy to treat TNBC. |
| Databáze: | OpenAIRE |
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