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Functional analysis of recurrent CDC20 promoter variants in human melanoma. | LitMetric

Functional analysis of recurrent CDC20 promoter variants in human melanoma.

Commun Biol

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

Published: November 2023

AI Article Synopsis

Article Abstract

Small nucleotide variants in non-coding regions of the genome can alter transcriptional regulation, leading to changes in gene expression which can activate oncogenic gene regulatory networks. Melanoma is heavily burdened by non-coding variants, representing over 99% of total genetic variation, including the well-characterized TERT promoter mutation. However, the compendium of regulatory non-coding variants is likely still functionally under-characterized. We developed a pipeline to identify hotspots, i.e. recurrently mutated regions, in melanoma containing putatively functional non-coding somatic variants that are located within predicted melanoma-specific regulatory regions. We identified hundreds of statistically significant hotspots, including the hotspot containing the TERT promoter variants, and focused on a hotspot in the promoter of CDC20. We found that variants in the promoter of CDC20, which putatively disrupt an ETS motif, lead to lower transcriptional activity in reporter assays. Using CRISPR/Cas9, we generated an indel in the CDC20 promoter in human A375 melanoma cell lines and observed decreased expression of CDC20, changes in migration capabilities, increased growth of xenografts, and an altered transcriptional state previously associated with a more proliferative and less migratory state. Overall, our analysis prioritized several recurrent functional non-coding variants that, through downregulation of CDC20, led to perturbation of key melanoma phenotypes.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10686982PMC
http://dx.doi.org/10.1038/s42003-023-05526-2DOI Listing

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