Inactivating Mutations of CUX1 Are Tumorigenic

Driver genes that are mutated at a low frequency are unlikely to be identified as significantly mutated in cancer genome studies. To identify low-frequency mutations affecting tumor suppressor genes, Wong and colleagues analyzed over 7,600 exome or genome sequences from 28 tumor types and searched for genes with a high rate of nonsense mutations, which would suggest selective pressure for loss of function. Among the genes identified was cut-like homeobox 1 (CUX1), a homeodomain-containing transcription factor gene with an overall mutation frequency of 1% to 5% across all tumor types. Inactivating insertions within Cux1 were common in a transposon-mediated mutagenesis screen for drivers of T-cell acute lymphoblastic leukemia (T-ALL) in mice, and depletion of the CUX1 ortholog cut in Drosophila markedly increased cell proliferation, providing further evidence that CUX1 is a tumor suppressor gene. Gene expression profiling following knockdown of CUX1 in T-ALL cells showed that the most highly downregulated gene was phosphoinositide-3-kinase (PI3K)- interacting protein 1 (PIK3IP1), an antagonist of PI3K catalytic activity, raising the possibility that loss of CUX1 may prevent transcription of PIK3IP1 and lead to activation of the PI3K pathway. Indeed, CUX1 directly bound the PIK3IP1 promoter and activated PIK3IP1 expression, and knockdown of CUX1 led to reduced PIK3IP1 levels and increased AKT phosphorylation that could be rescued by PIK3IP1 overexpression. Moreover, CUX1 knockdown or mutation conferred sensitivity to a pan-AKT or a dual PI3K/mTOR inhibitor, indicating that CUX1 loss leads to increased dependence on hyperactive PI3K–AKT signaling and suggesting that CUX1 mutations may be predictors of response to inhibitors of the PI3K–AKT pathway. Although other roles for CUX1 cannot be ruled out, these findings indicate that CUX1 is an evolutionarily conserved tumor suppressor gene mutated at a low frequency in human cancers that acts as an inhibitor of the PI3K pathway.

Wong CC, Martincorena I, Rust AG, Rashid M, Alifrangis C, Alexandrov LB, et al. Inactivating CUX1 mutations promote tumorigenesis. Nat Genet 2013 Dec 8 [Epub ahead of print].