Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34257283.
- Also identified by DOI 10.1038/s41467-021-24498-7 and PMC identifier 8277813.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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.
Medical subject headings
- Intracellular Signaling Peptides and Proteins
- Neoplastic Stem Cells
- Proto-Oncogene Proteins p21(ras)
- RNA-Binding Proteins