Interplay between PREX2 mutations and the PI3K pathway and its effect on epigenetic regulation of gene expression in NRAS-mutant melanoma.
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.
a Department of Genomic Medicine , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
Yonathan
Y
Lissanu Deribe
D000818:Animals; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D020558:GTP Phosphohydrolases / Q000235:genetics*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D008745:Methylation; D051379:Mice; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; D006657:Histones; D008565:Membrane Proteins; C490712:PREX2 protein, human; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
PI3K; PREX2; RAC1; epigenetics; genomic imprinting; mouse models of cancer