Interplay between PREX2 mutations and the PI3K pathway and its effect on epigenetic regulation of gene expression in NRAS-mutant melanoma

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)178-185
Number of pages8
JournalSmall GTPases
Volume7
Issue number3
DOIs
StatePublished - Jul 2 2016

Fingerprint

Gene Expression Regulation
Phosphatidylinositol 3-Kinases
Epigenomics
Gene expression
Melanoma
Mutation
Histone Code
Cells
PTEN Phosphohydrolase
Genomic Imprinting
Guanine Nucleotide Exchange Factors
Cell proliferation
DNA Methylation
Histones
Machinery
Cell Cycle
Proteins
Adenocarcinoma
Cell Proliferation
DNA

Keywords

  • PI3K
  • PREX2
  • RAC1
  • epigenetics
  • genomic imprinting
  • mouse models of cancer

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Cite this

@article{6897b5ea5031456e84181b218c9e3dbd,
title = "Interplay between PREX2 mutations and the PI3K pathway and its effect on epigenetic regulation of gene expression in NRAS-mutant melanoma",
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.",
keywords = "PI3K, PREX2, RAC1, epigenetics, genomic imprinting, mouse models of cancer",
author = "{Lissanu Deribe}, Yonathan",
year = "2016",
month = "7",
day = "2",
doi = "10.1080/21541248.2016.1178366",
language = "English (US)",
volume = "7",
pages = "178--185",
journal = "Small GTPases",
issn = "2154-1248",
publisher = "Landes Bioscience",
number = "3",

}

TY - JOUR

T1 - Interplay between PREX2 mutations and the PI3K pathway and its effect on epigenetic regulation of gene expression in NRAS-mutant melanoma

AU - Lissanu Deribe, Yonathan

PY - 2016/7/2

Y1 - 2016/7/2

N2 - 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.

AB - 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.

KW - PI3K

KW - PREX2

KW - RAC1

KW - epigenetics

KW - genomic imprinting

KW - mouse models of cancer

UR - http://www.scopus.com/inward/record.url?scp=84966705366&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84966705366&partnerID=8YFLogxK

U2 - 10.1080/21541248.2016.1178366

DO - 10.1080/21541248.2016.1178366

M3 - Article

C2 - 27111337

AN - SCOPUS:84966705366

VL - 7

SP - 178

EP - 185

JO - Small GTPases

JF - Small GTPases

SN - 2154-1248

IS - 3

ER -