Alternative splicing modulates the expression of many oncogene and tumor-suppressor isoforms. We have tested whether some alternative splicing factors are involved in cancer. We found that the splicing factor SF2/ASF is upregulated in various human tumors, in part due to amplification of its gene, SFRS1. Moreover, slight overexpression of SF2/ASF is sufficient to transform immortal rodent fibroblasts, which form sarcomas in nude mice. We further show that SF2/ASF controls alternative splicing of the tumor suppressor BIN1 and the kinases MNK2 and S6K1. The resulting BIN1 isoforms lack tumor-suppressor activity; an isoform of MNK2 promotes MAP kinase–independent eIF4E phosphorylation; and an unusual oncogenic isoform of S6K1 recapitulates the transforming activity of SF2/ASF. Knockdown of either SF2/ASF or isoform-2 of S6K1 is sufficient to reverse transformation caused by the overexpression of SF2/ASF in vitro and in vivo. Thus, SF2/ASF can act as an oncoprotein and is a potential target for cancer therapy.
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We thank G. Dreyfuss (University of Pennsylvania) for antibodies to hnRNP A1 and A2; D. Pant for advice on statistical tests; A. Rosenberg, M. Nolan and S. Muthuswamy (Cold Spring Harbor Laboratory) for the breast-cancer cell lines; and M. Hemann, L. Zender, R.-M. Xu, A. Neuwald, S. Powers and R. Lucito for helpful discussions. This work was supported by grant CA13106 from the US National Cancer Institute.
The authors declare no competing financial interests.
Amplification and overexpression of SF2/ASF in cancer cell lines, and correlation with alternative splicing of its targets. (PDF 667 kb)
Analysis of transduced splicing factor levels in mouse, rat and human cell lines. (PDF 652 kb)
Alternative splicing of mouse Rps6kb1 and primary structure of the two S6K1 isoforms. (PDF 29 kb)
Correlation between SF2/ASF expression and S6K1 isoform ratios in 50 lung tumors. (PDF 84 kb)
Knockdown of isoform-2 of S6K1 reverses NCI-H460 cell transformation. (PDF 355 kb)
Alternative splicing changes induced by overexpression or knockdown of specific splicing factors. (PDF 116 kb)
Primers, probes and shRNA templates. (PDF 133 kb)
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Karni, R., de Stanchina, E., Lowe, S. et al. The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol 14, 185–193 (2007) doi:10.1038/nsmb1209
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