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

Andrew T Ludlow1,2, Mandy Sze Wong3,4, Jerome D Robin3,5

  • 1Department of Cell Biology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA. atludlow@umich.edu.

Nature Communications
|August 8, 2018
PubMed

Insights

Alternative splicing dysregulation in cancer impacts telomerase reactivation. NOVA1 knockdown shifts hTERT splicing, reducing telomerase activity and cancer cell growth, offering potential therapeutic targets.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Alternative splicing is frequently dysregulated in cancer.
  • Telomerase reactivation in cancer involves splicing of TERT transcripts to produce full-length (FL) TERT.
  • Splicing factors that regulate FL hTERT production are not well understood.

Purpose of the Study:

  • To identify splicing factors that regulate telomerase activity and telomere length.
  • To investigate the role of NOVA1 in hTERT splicing and cancer progression.

Main Methods:

  • Conducted a siRNA minigene reporter screen to identify splicing factors.
  • Utilized a lung cancer cell bioinformatics approach.
  • Performed genome engineering experiments to validate NOVA1 function.

Main Results:

  • Identified NOVA1 as a key splicing factor that promotes FL hTERT production.
  • NOVA1 knockdown shifted hTERT splicing to non-catalytic isoforms, reduced telomerase activity, and shortened telomeres.
  • NOVA1 knockdown inhibited cancer cell growth in vitro and in xenografts.

Conclusions:

  • NOVA1 promotes exon inclusion in the hTERT reverse transcriptase domain, leading to FL hTERT transcripts.
  • Targeting dysregulated splicing factors like NOVA1 may offer novel therapeutic strategies for cancer.

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