title: Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15.
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).
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ting
authors.identifier: 0000-0003-3370-367X
authors.initials: T
authors.lastname: Han
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Maria
authors.identifier: 0000-0002-1590-901X
authors.initials: M
authors.lastname: Goralski
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Nicholas
authors.identifier: 0000-0001-5855-7977
authors.initials: N
authors.lastname: Gaskill
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Emanuela
authors.identifier: 0000-0002-1490-6642
authors.initials: E
authors.lastname: Capota
authors.affiliation: Quantitative Biomedical Research Center, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jiwoong
authors.identifier: 0000-0003-0220-9329
authors.initials: J
authors.lastname: Kim
authors.affiliation: Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Tabitha C
authors.identifier: 0000-0001-5206-9243
authors.initials: TC
authors.lastname: Ting
authors.affiliation: Quantitative Biomedical Research Center, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yang
authors.identifier: 0000-0001-9456-1762
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Noelle S
authors.identifier: 0000-0003-1894-5742
authors.initials: NS
authors.lastname: Williams
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. deepak.nijhawan@utsouthwestern.edu.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Deepak
authors.identifier: 0000-0001-6253-4268
authors.initials: D
authors.lastname: Nijhawan
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D012326:RNA Splicing / Q000187:drug effects*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; C556016:DCAF17 protein, human; C084105:HCC1 autoantigen; C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D013449:Sulfonamides; D043743:Ubiquitin-Protein Ligase Complexes; D046988:Proteasome Endopeptidase Complex