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.
authors: Department of Molecular Pharmacology and Chemistry, Antitumor Assessment Core Facility, Breast Cancer Service, Memorial Sloan-Kettering Cancer Center Imaging Center, and Experimental Therapeutic Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Francesca
authors: F
authors: Zammarchi
authors: Elisa
authors: E
authors: de Stanchina
authors: Eirini
authors: E
authors: Bournazou
authors: Teerawit
authors: T
authors: Supakorndej
authors: Kathryn
authors: K
authors: Martires
authors: Elyn
authors: E
authors: Riedel
authors: Adriana D
authors: AD
authors: Corben
authors: Jacqueline F
authors: JF
authors: Bromberg
authors: Luca
authors: L
authors: Cartegni
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D046228:Microarray Analysis; D009369:Neoplasms / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D016376:Oligonucleotides, Antisense; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human