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

Autor: Chen WC; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA., To MD; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA., Westcott PMK; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.; MIT Koch Institute for Integrative Cancer Research, Cambridge, MA, USA., Delrosario R; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA., Kim IJ; Guardant Health, Redwood City, California, USA., Philips M; NYU Cancer Institute, NYU School of Medicine, New York, NY, USA., Tran Q; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA., Bollam SR; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA., Goodarzi H; Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA., Bayani N; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA., Mirzoeva O; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA., Balmain A; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA. allan.balmain@ucsf.edu.; Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA. allan.balmain@ucsf.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Jul 13; Vol. 12 (1), pp. 4288. Date of Electronic Publication: 2021 Jul 13.
DOI: 10.1038/s41467-021-24498-7
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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