Identification of FUBP1 as a Long Tail Cancer Driver and Widespread Regulator of Tumor Suppressor and Oncogene Alternative Splicing

Comprehensive sequencing approaches have allowed for the identification of the most frequent contributors to cancer, known as drivers. They have also revealed a class of mutations in understudied, infrequently altered genes, referred to as “long tail” (LT) drivers. A key challenge has been to find clinically relevant LT drivers and to understand how they cooperate to drive disease. Here, we identified far upstream binding protein 1 (FUBP1) as an LT driver using an in vivo CRISPR screen. FUBP1 cooperates with other tumor suppressor genes to transform mammary epithelial cells by disrupting cellular differentiation and tissue architecture. Mechanistically, FUBP1 participates in regulating N6-methyladenosine (m6A) RNA methylation, and its loss leads to global changes in RNA splicing and widespread expression of aberrant driver isoforms. These findings suggest that somatic alteration of a single gene involved in RNA splicing and m6A methylation can produce the necessary panoply of contributors for neoplastic transformation. [Display omitted] •A combinatorial CRISPR screen identifies clinically relevant cooperating cancer genes•FUBP1 loss cooperates with PTEN loss to promote tumor growth•FUBP1−/− cells undergo widespread alternative splicing and reduced m6A methylation•Loss of one gene can alter the transcriptional landscape to promote tumorigenicity Elman et al. identify FUBP1 as a long tail cancer driver using a combinatorial CRISPR/Cas9 screen. FUBP1 and PTEN cooperate to transform mammary epithelial cells by disrupting cellular differentiation and tissue architecture. FUBP1−/− cells exhibit decreased m6A RNA methylation, leading to widespread expression of aberrant driver isoforms.