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Science. 2017 Apr 28;356(6336). pii: eaal3755. doi: 10.1126/science.aal3755. Epub 2017 Mar 16.

Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15.

Author information

1
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3
Quantitative Biomedical Research Center, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
4
Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5
Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
6
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. deepak.nijhawan@utsouthwestern.edu.

Abstract

Indisulam is an aryl sulfonamide drug with selective anticancer activity. Its mechanism of action and the basis for its selectivity have so far been unknown. Here we show that indisulam promotes the recruitment of RBM39 (RNA binding motif protein 39) to the CUL4-DCAF15 E3 ubiquitin ligase, leading to RBM39 polyubiquitination and proteasomal degradation. Mutations in RBM39 that prevent its recruitment to CUL4-DCAF15 increase RBM39 stability and confer resistance to indisulam's cytotoxicity. RBM39 associates with precursor messenger RNA (pre-mRNA) splicing factors, and inactivation of RBM39 by indisulam causes aberrant pre-mRNA splicing. Many cancer cell lines derived from hematopoietic and lymphoid lineages are sensitive to indisulam, and their sensitivity correlates with DCAF15 expression levels. Two other clinically tested sulfonamides, tasisulam and chloroquinoxaline sulfonamide, share the same mechanism of action as indisulam. We propose that DCAF15 expression may be a useful biomarker to guide clinical trials of this class of drugs, which we refer to as SPLAMs (splicing inhibitor sulfonamides).

Comment in

PMID:
28302793
DOI:
10.1126/science.aal3755
[Indexed for MEDLINE]

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