Abstract
Anticancer sulfonamides produce aberrant splicing by inducing degradation of the splicing factor RBM39.
Major finding: Anticancer sulfonamides produce aberrant splicing by inducing degradation of the splicing factor RBM39.
Mechanism: The sulfonamides promote proteasomal degradation of RBM39 via recruitment to the CUL4–DCAF15 E3 ligase.
Impact: Therapeutic targeting of CUL4–DCAF15 may promote selective protein degradation in cancer.
The aryl sulfonamide drugs E7820, indisulam, and chloroquinoxaline sulfonamide are toxic to a subset of cancer cell lines and achieve clinical responses in a small subset of patients with advanced solid tumors. However, their mechanisms of action are unknown. Using proteomic profiling, Uehara and colleagues found that aryl sulfonamide drugs promoted proteasomal degradation of the U2AF-related splicing factor RBM39 (also known as CAPERα) in human colorectal carcinoma and myelogenous leukemia cell lines. Mechanistically, treatment with aryl sulfonamide drugs resulted in recruitment of RBM39 to the CUL4–DCAF15 E3 ubiquitin ligase, where it was polyubiquitinated and targeted for proteasomal degradation. CRISPR/Cas9-mediated depletion of DCAF15 or mutations in RBM39 that disrupted RBM39 recruitment to CUL4–DCAF15 enhanced the stability of RBM39 and conferred resistance to aryl sulfonamides, indicating that RBM39 is essential for the antitumor effects of these drugs. Further, RBM39 depletion resulted in alternative splicing of VEGFA as well as changes in expression of a number of target mRNAs, suggesting that aryl sulfonamide–mediated RBM39 degradation may promote aberrant pre-mRNA splicing. Collectively, these findings reveal a mechanism by which aryl sulfonamide drugs exert anticancer effects via targeting of RBM39, which is otherwise considered to be undruggable, and suggest that chemical intervention in protein homeostasis or small molecule–induced selective protein degradation may be therapeutic strategies to treat patients with cancer.
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