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

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

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).

Publication types

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

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Pharmacological / metabolism*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics
  • Humans
  • Mice
  • Mice, Knockout
  • Molecular Targeted Therapy*
  • Mutation
  • Neoplasms / drug therapy*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis
  • RNA Splicing / drug effects*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Sulfonamides / adverse effects
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use
  • Ubiquitin-Protein Ligase Complexes / metabolism*
  • Ubiquitination
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Biomarkers, Pharmacological
  • DCAF17 protein, human
  • HCC1 autoantigen
  • N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide
  • Nuclear Proteins
  • RNA-Binding Proteins
  • Sulfonamides
  • Ubiquitin-Protein Ligase Complexes
  • Proteasome Endopeptidase Complex