NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer

Nat Commun. 2018 Aug 6;9(1):3112. doi: 10.1038/s41467-018-05582-x.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Animals
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cell Line, Tumor
  • Computational Biology
  • Gene Deletion
  • Gene Silencing
  • Genetic Engineering
  • Genome, Human
  • HeLa Cells
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Mice
  • Mutation
  • Neoplasm Transplantation
  • Phenotype
  • Protein Binding
  • RNA, Small Interfering / metabolism
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Telomerase / genetics*
  • Telomerase / metabolism
  • Telomere / ultrastructure

Substances

  • NOVA1 protein, human
  • Nova1 protein, mouse
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • TERT protein, human
  • Telomerase
  • Tert protein, mouse