Targeting KRAS4A Splicing Through the RBM39/DCAF15 Pathway Inhibits Cancer Stem Cells

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Jul 14

PMID 34257283

Citations 24

Authors

Wei-Ching Chen

Minh D To

Peter M K Westcott

Reyno Delrosario

Il-Jin Kim

Mark Philips

Quan Tran

Saumya R Bollam

Hani Goodarzi

Nora Bayani

Olga Mirzoeva

Allan Balmain

Affiliations

Soon will be listed here.

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.

Citing Articles

Targeting RNA splicing modulation: new perspectives for anticancer strategy?.

Lv X, Sun X, Gao Y, Song X, Hu X, Gong L J Exp Clin Cancer Res. 2025; 44(1):32.

PMID: 39885614 PMC: 11781073. DOI: 10.1186/s13046-025-03279-w.

Targeting KRAS: from metabolic regulation to cancer treatment.

Shi Y, Zheng H, Wang T, Zhou S, Zhao S, Li M Mol Cancer. 2025; 24(1):9.

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RNA-binding motif protein RBM39 enhances the proliferation of gastric cancer cells by facilitating an oncogenic splicing switch in MRPL33.

Lu C, Li J, Li D, Wang Y, Jiang X, Ma J Acta Pharmacol Sin. 2025; .

PMID: 39753980 DOI: 10.1038/s41401-024-01431-4.

IsopretGO-analysing and visualizing the functional consequences of differential splicing.

Karlebach G, Hansen P, Kohler K, Robinson P NAR Genom Bioinform. 2024; 6(4):lqae165.

PMID: 39660256 PMC: 11630322. DOI: 10.1093/nargab/lqae165.

Targeting RBM39 suppresses tumor growth and sensitizes osteosarcoma cells to cisplatin.

Wang J, Zheng L, Chen W, Zhang X, Lv D, Zeng C Oncogene. 2024; 44(9):575-586.

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