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Cancer-associated regulation of alternative splicing

Nature Structural & Molecular Biology volume 16, pages 670–676 (2009)Cite this article

Abstract

Alternative splicing of pre-mRNA increases the diversity of protein functions. Here we show that about half of all active alternative splicing events in ovarian and breast tissues are changed in tumors, and many seem to be regulated by a single factor; sequence analysis revealed binding sites for the RNA binding protein FOX2 downstream of one-third of the exons skipped in cancer. High-resolution analysis of FOX2 binding sites defined the precise positions relative to alternative exons at which the protein may function as either a silencer or an enhancer. Most of the identified targets were shifted in the same direction by FOX2 depletion in cell lines as they were in breast and ovarian cancer tissues. Notably, we found expression of FOX2 itself is downregulated in ovarian cancer and its splicing is altered in breast cancer samples. These results suggest that the decreased expression of FOX2 in cancer tissues modulates splicing and controls proliferation.

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Figure 1: Screening strategy for the identification of cancer-associated ASEs.
Figure 2: Heatmap representation of isoform ratios for the association screen in normal and cancerous breast and ovary tissue samples.
Figure 3: Splicing profiles of normal and cancerous breast and ovary tissue.
Figure 4: RNA maps of FOX2-induced splicing shifts.
Figure 5: FOX2-regulated alternative splicing in cancer.

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Acknowledgements

Thanks to D. Namroud, C. Richard and M. Lévesque for administrative support. Thanks also to J.-P. Brosseau, B. Bell and H. Nwilati for comments on the manuscript. This work was funded by a grant from Genome Canada and Génome Québec. B.C. is supported by a Canada Research Chair in Functional Genomics. S.A.E. is supported by the Fonds de la Recherche en Santé du Québec (FRSQ) Chercheur National program. Tumor banking was supported by the Banque de tissus et de données of the Réseau de Recherche sur le Cancer of the FRSQ.

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  1. Laboratoire de génomique fonctionnelle de l'Université de Sherbrooke, Sherbrooke, Québec, Canada

    Julian P Venables, Roscoe Klinck, ChuShin Koh, Julien Gervais-Bird, Anne Bramard, Lyna Inkel, Mathieu Durand, Sonia Couture, Ulrike Froehlich, Elvy Lapointe, Jean-François Lucier, Philippe Thibault, Claudine Rancourt, Karine Tremblay, Panagiotis Prinos, Benoit Chabot & Sherif Abou Elela

  2. Département de microbiologie et d'infectiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada

    Benoit Chabot & Sherif Abou Elela

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Contributions

J.P.V., R.K., P.P., B.C. and S.A.E. designed experiments, analyzed data and participated in the writing of the paper; K.T. designed and supervised experiments; C.R. selected and provided tissues; A.B., L.I., M.D., S.C., U.F. and E.L. carried out experiments; C.K., J.G.-B., J.-F.L. and P.T. analyzed data.

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Correspondence to Sherif Abou Elela.

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Venables, J., Klinck, R., Koh, C. et al. Cancer-associated regulation of alternative splicing. Nat Struct Mol Biol 16, 670–676 (2009). https://doi.org/10.1038/nsmb.1608

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