Year: 2021
Type: dissertation
Abstract: Determining drivers of metastasis is necessary to identify novel drugs targeting melanoma progression and improve prognoses. Herein, we study the role of transcription factor AP-2Alpha during metastatic progression of melanoma. We found that AP-2Alpha facilitates melanoma metastasis through transcriptional activation of genes within the E2F pathways. This is accomplished by an interaction with the Nucleosome Remodeling and Deacetylase (NuRD) Complex which results in promoter nucleosome hyper-acetylation and transcriptional activation of EZH2, a gene within the E2F pathways encoding a pro-metastatic Histone H3K27 methyltransferase. Analysis of a metastatic melanoma mouse model shows Tfap2a High cell populations arise from melanocyte stem cells during melanogenesis and exhibit induction of AP-2Alpha target genes within the E2F pathways. We found tazemetostat, an FDA-approved and highly specific EZH2 inhibitor, substantially reduced anchorage independent colony formation of melanoma cell lines and patient derived xenografts, an effect dependent on AP-2Alpha. Further, EZH2 inhibition in vivo elicited heritable anti-metastatic effects of melanoma xenografts. We further determined AP-2Alpha transcriptionally represses genes through novel occupancy of GAA/TTC-trinucleotide repeat microsatellites, DNA elements of previously unknown significance. The findings support a novel pro-metastatic function of AP-2Alpha in melanoma.
DOI: 10.17077/etd.005774
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4252461435