SRRM1 coordinates an alternative splicing program that promotes expression of oncogenic protein isoforms.
The alternative splicing of the adapter protein NUMB is dysregulated in multiple cancer types, regulating its functional divergence towards either tumor suppression or oncogenesis in an isoform-dependant manner. Here we utilized a NUMB exon 9 (E9) splicing reporter in a genome-wide CRISPR screen to identify splicing regulators SRRM1 and SRSF11 that promote NUMB oncogenic splicing in colorectal, lung and breast cancer cell lines. We show that SRRM1 and SRSF11 share common protein interactors, RNA targets and effects on an oncogenic splicing program which favors the expression of pro-tumorigenic isoforms. In addition to NUMB E9, SRRM1 regulates cancer-associated splicing events in genes encoding signaling proteins, transcription factors and actin cytoskeleton regulators, many of which are also developmentally regulated, including CD44, MKNK2, ECT2, DIAPH1, KAT5, TCF7L2, FOXM1 and TBX3. Loss of SRRM1 in colorectal and lung cancer cells reduces cell proliferation, colony formation and invasion capabilities, as well as expression of tumour promoters Cyclin D1, Notum, and PRDX2. Our data indicate that SRRM1 regulation of alternative splicing represents a node to target multiple properties of malignant cells, with broad effects on cellular signaling, proliferation, EMT, apoptosis resistance and stemness.