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

Ting Han, Maria Goralski, Nicholas Gaskill, Emanuela Capota, Jiwoong Kim, Tabitha C. Ting, Yang Xie, Noelle S. Williams, Deepak Nijhawan

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Indisulam is an aryl sulfonamide drug with selective anticancer activity. Its mechanism of action and the basis for its selectivity are 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 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 sulfanomides, tasisulam and CQS, 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).

Original languageEnglish (US)
Pages (from-to)1-21
Number of pages21
JournalScience
DOIs
StateAccepted/In press - Mar 16 2017

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RNA-Binding Proteins
Sulfonamides
Proteolysis
RNA Precursors
N-((5-bromo-2-thienyl)sulfonyl)-2,4-dichlorobenzamide
Ubiquitin-Protein Ligases
Protein Stability
Pharmaceutical Preparations
N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide
RNA-Binding Motifs
Biomarkers
Clinical Trials
Cell Line
Mutation
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. / Han, Ting; Goralski, Maria; Gaskill, Nicholas; Capota, Emanuela; Kim, Jiwoong; Ting, Tabitha C.; Xie, Yang; Williams, Noelle S.; Nijhawan, Deepak.

In: Science, 16.03.2017, p. 1-21.

Research output: Contribution to journalArticle

Han, Ting ; Goralski, Maria ; Gaskill, Nicholas ; Capota, Emanuela ; Kim, Jiwoong ; Ting, Tabitha C. ; Xie, Yang ; Williams, Noelle S. ; Nijhawan, Deepak. / Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. In: Science. 2017 ; pp. 1-21.
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abstract = "Indisulam is an aryl sulfonamide drug with selective anticancer activity. Its mechanism of action and the basis for its selectivity are 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 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 sulfanomides, tasisulam and CQS, 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).",
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AU - Goralski, Maria

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AU - Kim, Jiwoong

AU - Ting, Tabitha C.

AU - Xie, Yang

AU - Williams, Noelle S.

AU - Nijhawan, Deepak

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AB - Indisulam is an aryl sulfonamide drug with selective anticancer activity. Its mechanism of action and the basis for its selectivity are 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 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 sulfanomides, tasisulam and CQS, 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).

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