Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells

Autor: 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
Jazyk: angličtina
Rok vydání: 2021
Předmět:
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
Zdroj: Nature Communications
Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021)
Nature communications, vol 12, iss 1
ISSN: 2041-1723
Popis: 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.
Databáze: OpenAIRE
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