Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells
| العنوان: | Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells |
|---|---|
| المؤلفون: | Mark R. Philips, Il-Jin Kim, Reyno Delrosario, Saumya R. Bollam, Peter M. K. Westcott, Hani Goodarzi, Olga K. Mirzoeva, Minh D. To, Wei-Ching Chen, Allan Balmain, Nora Bayani, Quan Tran |
| المصدر: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021) Nature communications, vol 12, iss 1 |
| بيانات النشر: | Nature Publishing Group UK, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, General Physics and Astronomy, medicine.disease_cause, Polymerase Chain Reaction, Mice, 0302 clinical medicine, Stem Cell Research - Nonembryonic - Human, 2.1 Biological and endogenous factors, Aetiology, Cancer genetics, Cancer, Mice, Knockout, Multidisciplinary, Blotting, Cancer stem cells, Intracellular Signaling Peptides and Proteins, RNA-Binding Proteins, Flow Cytometry, 030220 oncology & carcinogenesis, RNA splicing, Neoplastic Stem Cells, Heterografts, Stem Cell Research - Nonembryonic - Non-Human, KRAS, Western, Transcription, Gene isoform, Knockout, Science, Blotting, Western, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Cancer stem cell, Genetics, medicine, Animals, Humans, Cell Proliferation, A549 cell, Oncogene, Human Genome, General Chemistry, Stem Cell Research, medicine.disease, 030104 developmental biology, A549 Cells, Unfolded protein response, Cancer research |
| الوصف: | The commonly mutated human KRAS oncogene encodes two distinct KRAS4A and KRAS4B proteins generated by differential splicing. We demonstrate here that coordinated regulation of both isoforms through control of splicing is essential for development of Kras mutant tumors. The minor KRAS4A isoform is enriched in cancer stem-like cells, where it responds to hypoxia, while the major KRAS4B is induced by ER stress. KRAS4A splicing is controlled by the DCAF15/RBM39 pathway, and deletion of KRAS4A or pharmacological inhibition of RBM39 using Indisulam leads to inhibition of cancer stem cells. Our data identify existing clinical drugs that target KRAS4A splicing, and suggest that levels of the minor KRAS4A isoform in human tumors can be a biomarker of sensitivity to some existing cancer therapeutics. Kras is frequently mutated in lung cancer and two isoforms are generated via alternative splicing. Here, the authors show that the two isoforms have divergent roles in cancer stem cells and the main tumour cell population, which are regulated by hypoxia and endoplasmic reticulum stress. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2041-1723 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::427008964cbd7475c096e5e574e7f68f http://europepmc.org/articles/PMC8277813 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....427008964cbd7475c096e5e574e7f68f |
| قاعدة البيانات: | OpenAIRE |
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