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The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells

Oncogene volume 33, pages 3794–3802 (2014)Cite this article

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Abstract

Splicing abnormalities have profound impact in human cancer. Several splicing factors, including SAM68, have pro-oncogenic functions, and their increased expression often correlates with human cancer development and progression. Herein, we have identified using mass spectrometry proteins that interact with endogenous SAM68 in prostate cancer (PCa) cells. Among other interesting proteins, we have characterized the interaction of SAM68 with SND1, a transcriptional co-activator that binds spliceosome components, thus coupling transcription and splicing. We found that both SAM68 and SND1 are upregulated in PCa cells with respect to benign prostate cells. Upregulation of SND1 exerts a synergic effect with SAM68 on exon v5 inclusion in the CD44 mRNA. The effect of SND1 on CD44 splicing required SAM68, as it was compromised after knockdown of this protein or mutation of the SAM68-binding sites in the CD44 pre-mRNA. More generally, we found that SND1 promotes the inclusion of CD44 variable exons by recruiting SAM68 and spliceosomal components on CD44 pre-mRNA. Inclusion of the variable exons in CD44 correlates with increased proliferation, motility and invasiveness of cancer cells. Strikingly, we found that knockdown of SND1, or SAM68, reduced proliferation and migration of PCa cells. Thus, our findings strongly suggest that SND1 is a novel regulator of alternative splicing that promotes PCa cell growth and survival.

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Acknowledgements

We wish to thank Dr Roberta Busà for suggestions with chromatin immunoprecipitation experiments and Dr Maria Loiarro for assistance with luciferase reporter assays. This work was supported by the Association for International Cancer Research (AICR grant no. 12-0150 to CS) and the Associazione Italiana Ricerca sul Cancro (AIRC grant no. 10348 to CS and MFAG no. 11658 to MPP).

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Authors and Affiliations

  1. Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy

    M Cappellari, P Bielli & C Sette

  2. Laboratory of Neuroembryology, Fondazione Santa Lucia, Rome, Italy

    M Cappellari, P Bielli & C Sette

  3. Laboratory of Cellular and Molecular Neurobiology, Fondazione Santa Lucia, Rome, Italy

    M P Paronetto

  4. Department of Health Sciences, University of Rome Foro Italico, Rome, Italy

    M P Paronetto

  5. Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases ‘Lazzaro Spallanzani’, Rome, Italy

    F Ciccosanti & G M Fimia

  6. Laboratory of Molecular Immunology, School of Medicine and Institute of Biomedical Technology, Biomeditech, University of Tampere, Tampere, Finland

    J Saarikettu & O Silvennoinen

  7. Department of Internal Medicine, Tampere University Hospital, Tampere, Finland

    O Silvennoinen

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  1. M Cappellari
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Correspondence to C Sette.

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Cappellari, M., Bielli, P., Paronetto, M. et al. The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells. Oncogene 33, 3794–3802 (2014). https://doi.org/10.1038/onc.2013.360

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