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

Nat Commun. 2021 Jul 13;12(1):4288. doi: 10.1038/s41467-021-24498-7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Blotting, Western
  • Cell Proliferation
  • Flow Cytometry
  • Heterografts
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Neoplastic Stem Cells / metabolism*
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*

Substances

  • DCAF15 protein, human
  • HCC1 autoantigen
  • Intracellular Signaling Peptides and Proteins
  • KRAS protein, human
  • RNA-Binding Proteins
  • Proto-Oncogene Proteins p21(ras)