Journal Article

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

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

2017

Overview

Typically, cancer drugs that help only a small number of patients in clinical trials are not pursued. This might change in a future world of precision medicine, where biomarkers will match specific drugs to the patients most likely to respond. Han et al. identified the mechanism of action of a cancer drug called indisulam, a sulfonamide tested previously in patients with solid tumors. Indisulam and related sulfonamides killed cells by disrupting precursor mRNA splicing. The drugs targeted a specific RNA splicing factor for degradation by “gluing” it to the CUL4-DCAF15 ubiquitin ligase. Experiments with cancer cell lines suggest that future clinical trials of these drugs should focus on leukemias and lymphomas with high DCAF15 expression levels. Science , this issue p. eaal3755 Sulfonamide drugs kill cancer cells by targeting a specific RNA splicing factor for degradation. 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).

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Amino Acid Substitution / Amino acids / Animals / Antibiotics / Anticancer properties / Antineoplastic Agents - adverse effects / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Antineoplastic drugs / Antitumor activity / Antitumor agents / Aromatic compounds / Binding / Biomarkers / Biomarkers, Pharmacological - metabolism / Cancer / Cell Line, Tumor / Clinical trials / Copy number / Cytotoxicity / Degradation / Drug Resistance, Neoplasm - genetics / Drugs / Exon skipping / Gene expression / Gene sequencing / Genetics / Genomes / Gluing / Hemopoiesis / Humans / Immunomodulation / Inactivation / Inhibitors / Leukemia / Literary Devices / Lymphoma / Medical research / Mice / Mice, Knockout / Molecular Targeted Therapy / Mutation / Narcotics / Neoplasms - drug therapy / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Patients / Precursors / Proteasome Endopeptidase Complex - metabolism / Proteasomes / Proteins / Proteolysis / Receptors / Recruitment / RESEARCH ARTICLE SUMMARY / Ribonucleic acid / Ribonucleic acids / RNA / RNA Splicing - drug effects / RNA-binding protein / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Selectivity / Sensitivity / Solid tumors / Splicing / Splicing factors / Sulfonamides / Sulfonamides - adverse effects / Sulfonamides - pharmacology / Sulfonamides - therapeutic use / Toxicity / Tumor cell lines / Tumors / Ubiquitin-protein ligase / Ubiquitin-Protein Ligase Complexes - metabolism / Ubiquitination / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation