title: Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma.
abstract: PREX2 (phosphatidylinositol-3,4,5-triphosphate-dependent Rac-exchange factor 2) is a PTEN (phosphatase and tensin homolog deleted on chromosome 10) binding protein that is significantly mutated in cutaneous melanoma and pancreatic ductal adenocarcinoma. Here, genetic and biochemical analyses were conducted to elucidate the nature and mechanistic basis of PREX2 mutation in melanoma development. By generating an inducible transgenic mouse model we showed an oncogenic role for a truncating PREX2 mutation (PREX2(E824)*) in vivo in the context of mutant NRAS. Using integrative cross-species gene expression analysis, we identified deregulated cell cycle and cytoskeleton organization as significantly perturbed biological pathways in PREX2 mutant tumors. Mechanistically, truncation of PREX2 activated its Rac1 guanine nucleotide exchange factor activity, abolished binding to PTEN and activated the PI3K (phosphatidyl inositol 3 kinase)/Akt signaling pathway. We further showed that PREX2 truncating mutations or PTEN deletion induces down-regulation of the tumor suppressor and cell cycle regulator CDKN1C (also known as p57(KIP2)). This down-regulation occurs, at least partially, through DNA hypomethylation of a differentially methylated region in chromosome 11 that is a known regulatory region for expression of the CDKN1C gene. Together, these findings identify PREX2 as a mediator of NRAS-mutant melanoma development that acts through the PI3K/PTEN/Akt pathway to regulate gene expression of a cell cycle regulator.
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; ylissanu@mdanderson.org lchin@mdanderson.org.
authors.forename: Yonathan
authors.initials: Y
authors.lastname: Lissanu Deribe
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborate Center for Cancer Medicine, Guangzhou 510060, China;
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Kunal
authors.initials: K
authors.lastname: Rai
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Luigi
authors.initials: L
authors.lastname: Nezi
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Samir B
authors.initials: SB
authors.lastname: Amin
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Chia-Chin
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Kadir C
authors.initials: KC
authors.lastname: Akdemir
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Mozhdeh
authors.initials: M
authors.lastname: Mahdavi
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Qian
authors.initials: Q
authors.lastname: Peng
authors.affiliation: Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Qing Edward
authors.initials: QE
authors.lastname: Chang
authors.affiliation: The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom;
authors.forename: Kirsti
authors.initials: K
authors.lastname: Hornigold
authors.affiliation: Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, 23955-6900 Saudi Arabia;
authors.forename: Stefan T
authors.initials: ST
authors.lastname: Arold
authors.affiliation: The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom;
authors.forename: Heidi C E
authors.initials: HC
authors.lastname: Welch
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; Broad Institute of MIT and Harvard, Boston, MA 02141.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, TX 77030; ylissanu@mdanderson.org lchin@mdanderson.org.
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
mesh_terms: D000818:Animals; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C490712:PREX2 protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: PI3K/Akt; PREX2; Rac1; melanoma; mouse models of cancer