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

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 and Jerry W. Shay
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Andrew T. Ludlow: UT Southwestern Medical Center
Mandy Sze Wong: UT Southwestern Medical Center
Jerome D. Robin: UT Southwestern Medical Center
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
Woodring E. Wright: UT Southwestern Medical Center
Jerry W. Shay: UT Southwestern Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05582-x

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