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.

Cappellari, M., Bielli, P., Paronetto, M., Ciccosanti, F., Fimia, G., Saarikettu, J., et al. (2014). The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells. ONCOGENE, 33(29), 3794-3802 [10.1038/onc.2013.360].

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

Bielli, P;SETTE, CLAUDIO
2014-07-17

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.
17-lug-2014
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/16 - ANATOMIA UMANA
English
Con Impact Factor ISI
Cell Movement; Exons; DNA-Binding Proteins; Humans; Cell Line, Tumor; Protein Binding; Transcriptional Activation; Antigens, CD44; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Nuclear Proteins; Alternative Splicing; Adaptor Proteins, Signal Transducing; RNA-Binding Proteins; RNA Polymerase II; Prostatic Neoplasms; Male
Cappellari, M., Bielli, P., Paronetto, M., Ciccosanti, F., Fimia, G., Saarikettu, J., et al. (2014). The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells. ONCOGENE, 33(29), 3794-3802 [10.1038/onc.2013.360].
Cappellari, M; Bielli, P; Paronetto, M; Ciccosanti, F; Fimia, G; Saarikettu, J; Silvennoinen, O; Sette, C
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/101481
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