NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30082712.
- Also identified by DOI 10.1038/s41467-018-05582-x and PMC identifier 6079032.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Alternative splicing is dysregulated in cancer and the reactivation of telomerase involves the splicing of TERT transcripts to produce full-length (FL) TERT. Knowledge about the splicing factors that enhance or silence FL hTERT is lacking. We identified splicing factors that reduced telomerase activity and shortened telomeres using a siRNA minigene reporter screen and a lung cancer cell bioinformatics approach. A lead candidate, NOVA1, when knocked down resulted in a shift in hTERT splicing to non-catalytic isoforms, reduced telomerase activity, and progressive telomere shortening. NOVA1 knockdown also significantly altered cancer cell growth in vitro and in xenografts. Genome engineering experiments reveal that NOVA1 promotes the inclusion of exons in the reverse transcriptase domain of hTERT resulting in the production of FL hTERT transcripts. Utilizing hTERT splicing as a model splicing event in cancer may provide new insights into potentially targetable dysregulated splicing factors in cancer.
Medical subject headings
- Alternative Splicing
- Carcinoma, Non-Small-Cell Lung
- Lung Neoplasms
- RNA-Binding Proteins
- Telomerase