title: ERK/MAPK Signaling Drives Overexpression of the Rac-GEF, PREX1, in BRAF- and NRAS-Mutant Melanoma.
abstract: Recently, we identified that PREX1 overexpression is critical for metastatic but not tumorigenic growth in a mouse model of NRAS-driven melanoma. In addition, a PREX1 gene signature correlated with and was dependent on ERK MAPK activation in human melanoma cell lines. In the current study, the underlying mechanism of PREX1 overexpression in human melanoma was assessed. PREX1 protein levels were increased in melanoma tumor tissues and cell lines compared with benign nevi and normal melanocytes, respectively. Suppression of PREX1 by siRNA impaired invasion but not proliferation in vitro PREX1-dependent invasion was attributable to PREX1-mediated activation of the small GTPase RAC1 but not the related small GTPase CDC42. Pharmacologic inhibition of ERK signaling reduced PREX1 gene transcription and additionally regulated PREX1 protein stability. This ERK-dependent upregulation of PREX1 in melanoma, due to both increased gene transcription and protein stability, contrasts with the mechanisms identified in breast and prostate cancers, in which PREX1 overexpression was driven by gene amplification and HDAC-mediated gene transcription, respectively. Thus, although PREX1 expression is aberrantly upregulated and regulates RAC1 activity and invasion in these three different tumor types, the mechanisms of its upregulation are distinct and context dependent.
  
  
  
  This study identifies an ERK-dependent mechanism that drives PREX1 upregulation and subsequent RAC1-dependent invasion in BRAF- and NRAS-mutant melanoma. Mol Cancer Res; 14(10); 1009-18. ©2016 AACR.
authors.affiliation: Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Meagan B
authors.initials: MB
authors.lastname: Ryan
authors.affiliation: Department of Dermatology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Finn
authors.affiliation: Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Pedone
authors.affiliation: Department of Dermatology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Thomas
authors.affiliation: Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. cjder@med.unc.edu adrienne_cox@med.unc.edu.
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Der
authors.affiliation: Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Department of Radiation Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. cjder@med.unc.edu adrienne_cox@med.unc.edu.
authors.forename: Adrienne D
authors.initials: AD
authors.lastname: Cox
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation; D000077484:Vemurafenib
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D007191:Indazoles; D007211:Indoles; D008565:Membrane Proteins; C453280:PREX1 protein, human; D010879:Piperazines; D011728:Pyridones; D011744:Pyrimidinones; C587178:SCH772984; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human