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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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TERT promoter mutations in melanoma render TERT expression dependent on MAPK pathway activation

Andrelou F Vallarelli1,2,3, P Sivaramakrishna Rachakonda4, Jocelyne André1,2

  • 1INSERM, U976, Skin Research Centre, Hôpital Saint-Louis, Paris, F-75010, France.

Oncotarget
|July 25, 2016
PubMed

Insights

TERT promoter mutations in cancer reactivate telomerase by creating ETS transcription factor binding sites. This links MAPK pathway activation from BRAF/NRAS mutations to TERT expression via ETS1.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Telomere maintenance is crucial for cancer cell immortality.
  • Telomerase re-activation in cancer was poorly understood.
  • TERT promoter mutations were recently discovered in various cancers.

Purpose of the Study:

  • To investigate the mechanism of TERT gene re-expression in melanoma.
  • To elucidate the link between TERT promoter mutations and MAPK pathway activation.

Main Methods:

  • Analysis of TERT expression in melanoma cell lines.
  • Investigation of transcription factor binding to the mutated TERT promoter.
  • Assessment of ETS1 phosphorylation and its role in TERT regulation.
  • Inhibition of ETS1 to determine its effect on TERT expression.

Main Results:

  • TERT promoter mutations create ETS transcription factor binding sites.
  • Melanoma cell lines with oncogenic BRAF or NRAS mutations show MAPK pathway activation.
  • Activated MAPK pathway leads to ETS1 phosphorylation and binding to the mutated TERT promoter.
  • ETS1 binding drives TERT re-expression; ETS1 inhibition reduces TERT expression.

Conclusions:

  • TERT promoter mutations directly link MAPK pathway activation to TERT gene re-expression in melanoma.
  • The transcription factor ETS1 is a key mediator in this process.
  • This mechanism provides insight into telomerase reactivation in cancer.
Keywords:
BRAFETS1MAPK pathwaymelanomatelomerase

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