Antitumorigenic potential of STAT3 alternative splicing modulation Journal Article
| Authors: | Zammarchi, F.; de Stanchina, E.; Bournazou, E.; Supakorndej, T.; Martires, K.; Riedel, E.; Corben, A. D.; Bromberg, J. F.; Cartegni, L. |
| Article Title: | Antitumorigenic potential of STAT3 alternative splicing modulation |
| Abstract: | Signal transducer and activator of transcription 3 (STAT3) plays a central role in the activation of multiple oncogenic pathways. Splicing variant STAT3β uses an alternative acceptor site within exon 23 that leads to a truncated isoform lacking the C-terminal transactivation domain. Depending on the context, STAT3β can act as a dominant-negative regulator of transcription and promote apoptosis. We show that modified antisense oligonucleotides targeted to a splicing enhancer that regulates STAT3 exon 23 alternative splicing specifically promote a shift of expression from STAT3α to STAT3β. Induction of endogenous STAT3β leads to apoptosis and cell-cycle arrest in cell lines with persistent STAT3 tyrosine phosphorylation compared with total STAT3 knockdown obtained by forced splicing-dependent nonsense-mediated decay (FSD-NMD). Comparison of the molecular effects of splicing redirection to STAT3 knockdown reveals a unique STAT3β signature, with a down-regulation of specific targets (including lens epithelium-derived growth factor, p300/CBP-associated factor, CyclinC, peroxisomal biogenesis factor 1, and STAT1β) distinct from canonical STAT3 targets typically associated with total STAT3 knockdown. Furthermore, similar in vivo redirection of STAT3 alternative splicing leads to tumor regression in a xenograft cancer model, demonstrating how pharmacological manipulation of a single key splicing event can manifest powerful antitumorigenic properties and validating endogenous splicing reprogramming as an effective cancer therapeutic approach. |
| Keywords: | controlled study; protein phosphorylation; unclassified drug; human cell; exon; nonhuman; validation process; protein function; animal cell; mouse; animal tissue; stat3 protein; apoptosis; animal experiment; animal model; in vivo study; antineoplastic activity; cancer cell culture; tumor regression; tyrosine; genetic manipulation; xenograft; alternative rna splicing; cell cycle arrest; down regulation; nuclear reprogramming; enzyme induction; cyclin c; antisense oligonucleotide; antisense therapy; histone acetyltransferase pcaf; peroxisomal biogenesis factor 1; stat1beta protein; stat3alpha protein; stat3beta protein; nonsense mediated mrna decay |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 108 |
| Issue: | 43 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2011-10-25 |
| Start Page: | 17779 |
| End Page: | 17784 |
| Language: | English |
| DOI: | 10.1073/pnas.1108482108 |
| PROVIDER: | scopus |
| PMCID: | PMC3203802 |
| PUBMED: | 22006329 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 9 December 2011" - "CODEN: PNASA" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
-
66Corben -
203Stubblefield -
142Bromberg -
18Cartegni -
347De Stanchina -
1Martires
Related MSK Work