Sulfonamide anti-cancer toxins target the RBM39 splicing factor for degradation by recruiting the DCAF15 ubiquitin ligase receptor

Indisulam is a small molecule with selective anti-cancer activity. The mechanism of action for indisulam and the basis for its selectivity is unknown. Here, we used a forward genetics strategy to discover that mutations in the gene encoding the RBM39 RNA binding protein cause indisulam resistance. Indisulam promotes interaction between RBM39 and the CUL4-DCAF15 E3 ubiquitin ligase, leading to polyubiquitination and proteasomal degradation of RBM39. Mutations in RBM39 reduce its interaction with CUL4-DCAF15, increase its stability and confer resistance to indisulam toxicity. RBM39 is essential for pre-mRNA splicing and inactivation of RBM39 by indisulam results in aberrant pre-mRNA splicing. Cancer cell lines originating from the hematopoietic and lymphoid tissue lineages frequently exhibit sensitivity to indisulam, and their response to indisulam can be predicted by the expression levels of DCAF15. Our studies reveal RBM39-DCAF15 as the target of indisulam, and identify DCAF15 expression as a potential biomarker to guide clinical trials of indisulam.