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Functional analysis of recurrent CDC20 promoter variants in human melanoma

Paula M Godoy1, Abimbola Oyedeji2,3, Jacqueline L Mudd2,3

  • 1Division of Medical Oncology, Department of Medicine and Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.

Communications Biology
|November 29, 2023
PubMed

Insights

Researchers identified new functional non-coding variants in melanoma, including in the CDC20 promoter. These variants alter gene expression, impacting melanoma cell behavior and tumor growth, offering potential new therapeutic targets.

Area of Science:

  • Genomics
  • Cancer Biology
  • Molecular Oncology

Background:

  • Non-coding variants significantly contribute to melanoma's genetic landscape, with over 99% of variations occurring in these regions.
  • While TERT promoter mutations are known, many regulatory non-coding variants remain functionally uncharacterized.
  • Understanding these variants is crucial for deciphering melanoma's complex gene regulatory networks.

Purpose of the Study:

  • To develop a pipeline for identifying recurrently mutated, putatively functional non-coding somatic variants in melanoma-specific regulatory regions.
  • To prioritize and functionally characterize novel regulatory variants beyond the well-known TERT promoter mutation.
  • To investigate the impact of CDC20 promoter variants on melanoma phenotypes.

Main Methods:

  • Development of a computational pipeline to identify mutation hotspots in non-coding regulatory regions of melanoma genomes.
  • Utilized reporter assays to assess the impact of CDC20 promoter variants on transcriptional activity.
  • Employed CRISPR/Cas9 gene editing in A375 melanoma cells to create a CDC20 promoter indel and analyze downstream effects.
  • Analyzed changes in CDC20 expression, cell migration, xenograft growth, and transcriptional state.

Main Results:

  • Identified hundreds of significant mutation hotspots in melanoma non-coding regions, including the TERT promoter and a novel hotspot in the CDC20 promoter.
  • Variants in the CDC20 promoter were shown to disrupt an ETS motif, reducing transcriptional activity.
  • CRISPR/Cas9-induced CDC20 promoter indel led to decreased CDC20 expression, altered cell migration, increased xenograft growth, and a shift towards a more proliferative transcriptional state.

Conclusions:

  • The study successfully prioritized recurrent functional non-coding variants in melanoma.
  • Downregulation of CDC20 by these variants perturbs key melanoma phenotypes, including proliferation and migration.
  • These findings highlight the importance of non-coding variants in melanoma pathogenesis and suggest potential therapeutic avenues targeting CDC20.

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