ArticleSmall GTPases2016
Interplay between PREX2 mutations and the PI3K pathway and its effect on epigenetic regulation of gene expression in NRAS-mutant melanoma.
Article in Small GTPases, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 11 citations in OpenAlex.
- Analysis of the mechanism ofThe Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2024Article
- Genetic Predisposition to Hepatocellular Carcinoma.Metabolites · 2022Review
- Cooperation between melanoma cell states promotes metastasis through heterotypic cluster formation.Developmental cell · 2021Article
- Phosphatidylinositol 3,4,5-Trisphosphate-Dependent Rac Exchanger 2 Protein Facilitates Glioma Progression via Akt and Stat3 Signaling.Journal of molecular neuroscience : MN · 2021Article
- Investigation of Genetic Mutations in High-risk and Low-risk Basal Cell Carcinoma in a Non-Caucasian Population by Whole Exome Sequencing.Acta dermato-venereologica · 2021Article
- The Molecular Landscape of Primary Acral Melanoma: A Multicenter Study of the Italian Melanoma Intergroup (IMI).International journal of molecular sciences · 2021Article
- Review
- Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications.Frontiers in molecular biosciences · 2020Review
- Targeting Rac and Cdc42 GEFs in Metastatic Cancer.Frontiers in cell and developmental biology · 2020Review
- A Case-Control Study of the Genetic Variability in Reactive Oxygen Species-Metabolizing Enzymes in Melanoma Risk.International journal of molecular sciences · 2018Article
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1 author at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
PREX2 is a PTEN interacting protein that is significantly mutated in melanoma and pancreatic ductal adenocarcinoma. Recently, we reported the mechanistic basis of melanomagenesis by PREX2 mutations. Truncating PREX2 mutations activate its guanine nucleotide exchange factor activity for its substrate RAC1. This leads to increased PI3K/AKT signaling associated with reduced DNA methylation and increased cell proliferation in NRAS-mutant melanoma. Here, we provide additional data that indicates a reciprocal regulation of PREX2 by PTEN whereby loss of PTEN results in a dramatic increase in expression of PREX2 at the protein level. Pharmacologic studies revealed destabilization of PREX2 by inhibition of PI3K/AKT signaling. Additionally, we provide data to show a selective decrease in a particular histone mark, H4 Lys20 trimethylation, in cells expressing PREX2 (E824*) truncating mutation globally and at the imprint control region of CDKN1C (also known as p57) and IGF2. The decrease in H4K20 trimethylation coupled with DNA hypomethylation at this particular locus is associated with genomic imprinting and regulation of expression of p57 and IGF2. Taken together, these results demonstrate the complex signaling mechanisms that involve PREX2, PI3K/AKT/PTEN and downstream epigenetic machinery to deregulate expression of key cell cycle regulators.
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