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

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…

• WF
  Welch Foundation

  Award: I-1879
• DR
  Damon Runyon Cancer Research Foundation

  Award: CI-68-13
• CP
  Cancer Prevention and Research Institute of Texas

  Award: RP150596
• LS
  Life Sciences Research Foundation