RBM5, 6, and 10 Differentially Regulate NUMB Alternative Splicing to Control Cancer Cell Proliferation

RBM5, a regulator of alternative splicing of apoptotic genes, and its highly homologous RBM6 and RBM10 are RNA-binding proteins frequently deleted or mutated in lung cancer. We report that RBM5/6 and RBM10 antagonistically regulate the proliferative capacity of cancer cells and display distinct positional effects in alternative splicing regulation. We identify the Notch pathway regulator NUMB as a key target of these factors in the control of cell proliferation. NUMB alternative splicing, which is frequently altered in lung cancer, can regulate colony and xenograft tumor formation, and its modulation recapitulates or antagonizes the effects of RBM5, 6, and 10 in cell colony formation. RBM10 mutations identified in lung cancer cells disrupt NUMB splicing regulation to promote cell growth. Our results reveal a key genetic circuit in the control of cancer cell proliferation. [Display omitted] •Antagonistic regulation of cell proliferation by highly related RNA-binding proteins•Distinct alternative splicing regulation networks by related RNA-binding proteins•NUMB alternative splicing is a key target of RBM5, 6, and 10 in cell proliferation•Lung cancer mutation in RBM10 causes misregulation of NUMB alternative splicing