Abstract
Stimulated cells and cancer cells have widespread shortening of mRNA 3’-untranslated regions (3’UTRs) and switches to shorter mRNA isoforms due to usage of more proximal polyadenylation signals (PASs) in introns and last exons. U1 snRNP (U1), vertebrates’ most abundant non-coding (spliceosomal) small nuclear RNA, silences proximal PASs and its inhibition with antisense morpholino oligonucleotides (U1 AMO) triggers widespread premature transcription termination and mRNA shortening. Here we show that low U1 AMO doses increase cancer cells’ migration and invasion in vitro by up to 500%, whereas U1 over-expression has the opposite effect. In addition to 3’UTR length, numerous transcriptome changes that could contribute to this phenotype are observed, including alternative splicing, and mRNA expression levels of proto-oncogenes and tumor suppressors. These findings reveal an unexpected role for U1 homeostasis (available U1 relative to transcription) in oncogenic and activated cell states, and suggest U1 as a potential target for their modulation.
Highlights
Stimulated cells and cancer cells have widespread shortening of messenger RNA (mRNA) 3’-untranslated regions (3’UTRs) and switches to shorter mRNA isoforms due to usage of more proximal polyadenylation signals (PASs) in introns and last exons
Widespread shortening of messenger RNA 3ʹuntranslated regions (3ʹUTRs) and switches to short mRNA isoforms is a common feature and contributing factor to cell stimulation, seen in immune cells and neurons, and oncogenicity[1,2,3,4,5,6]. These shortening events occur due to a shift in usage of more upstream polyadenylation signals (PASs) in the last exon and in introns. These PASs are generally silenced by U1 snRNP (U1), vertebrates’ most abundant non-coding small nuclear RNP, which is necessary for production of full-length RNA polymerase II transcripts from protein-coding genes and long non-coding RNAs7
We used standard in vitro assays to determine if moderate U1 inhibition has an effect on proliferation, migration, or invasion of cancer cells, which serve as quantitative measures of oncogenic phenotype
Summary
Stimulated cells and cancer cells have widespread shortening of mRNA 3’-untranslated regions (3’UTRs) and switches to shorter mRNA isoforms due to usage of more proximal polyadenylation signals (PASs) in introns and last exons. These shortening events occur due to a shift in usage of more upstream polyadenylation signals (PASs) in the last exon and in introns In quiescent cells, these PASs are generally silenced by U1 snRNP (U1), vertebrates’ most abundant non-coding small nuclear RNP, which is necessary for production of full-length RNA polymerase II transcripts from protein-coding genes and long non-coding RNAs7. The drastic PCPA from high U1 AMO in many genes obscures other effects that are more readily detected with low U1 AMO doses These changes include 3ʹUTR shortening (shifts to usage of more proximal PASs in tandem PASs) and the production of shorter mRNA isoforms from PAS usage in introns[9]. These changes are consistent with U1’s central role in splicing and telescripting, and include many with known functions in cancer
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