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

Author

Listed:
  • Andrew T. Ludlow

    (UT Southwestern Medical Center
    University of Michigan)

  • Mandy Sze Wong

    (UT Southwestern Medical Center
    Cold Spring Harbor Laboratories)

  • Jerome D. Robin

    (UT Southwestern Medical Center
    UMR125)

  • Kimberly Batten

    (UT Southwestern Medical Center)

  • Laura Yuan

    (UT Southwestern Medical Center)

  • Tsung-Po Lai

    (UT Southwestern Medical Center)

  • Nicole Dahlson

    (UT Southwestern Medical Center)

  • Lu Zhang

    (UT Southwestern Medical Center)

  • Ilgen Mender

    (UT Southwestern Medical Center)

  • Enzo Tedone

    (UT Southwestern Medical Center)

  • Mohammed E. Sayed

    (UT Southwestern Medical Center
    University of Michigan)

  • Woodring E. Wright

    (UT Southwestern Medical Center)

  • Jerry W. Shay

    (UT Southwestern Medical Center)

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.

Suggested Citation

  • Andrew T. Ludlow & Mandy Sze Wong & Jerome D. Robin & Kimberly Batten & Laura Yuan & Tsung-Po Lai & Nicole Dahlson & Lu Zhang & Ilgen Mender & Enzo Tedone & Mohammed E. Sayed & Woodring E. Wright & Je, 2018. "NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05582-x
    DOI: 10.1038/s41467-018-05582-x
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