Splicing regulation by USP39 deubiquitinase is essential for KRAS-driven cancer. Homo sapiens

KRAS is the most frequently mutated oncogene in human cancer, but its therapeutic targeting remains challenging. Here, we report a synthetic lethal screen with a library of deubiquitinases and identify USP39, which encodes an essential splicing factor, as a critical gene for the viability of KRAS-dependent cells. We show that the essentiality of USP39 for these cells is based on its critical role in splicing regulation, as splicing fidelity inhibitors also decrease preferentially the proliferation rate of KRAS-active cells. Moreover, depletion of DHX38, an USP39-interacting splicing factor, also reduces the viability of these cells. Furthermore, we show that USP39 is upregulated in lung and colon carcinomas and its expression correlates with KRAS levels and poor clinical outcome, supporting the oncogenic role of this deubiquitinase. Accordingly, our work provides critical information for the development of splicing-directed antitumor treatments and supports the potential of USP39-targeting strategies for the development of anticancer therapies. Overall design: RNA from control (transduced with empty pLKO-1 vector) and USP39-silenced A549 and H358 lung cancer cells was extracted and transcriptional profiling was obtained with GeneChip Human Exon 1.0 ST Arrays.