Regulation of NUMB alternative splicing by RBM5, RBM6 and RBM10 controls cancer cell proliferation. Homo sapiens

RBM5, a regulator of alternative splicing of apoptotic genes, and its close homologues, 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. Overall design: RNA from 3 biological replicates of knockdowns of RBM5, 6 and 10 and a control set were used. Changes between the control and knockdowns were measured based on using a splice-junction array (Affymetrix HJAY).