title: Oncogenic suppression of PHLPP1 in human melanoma.
abstract: Akt is constitutively activated in up to 70% of human melanomas and has an important role in the pathogenesis of the disease. However, little is known about protein phosphatases that dephosphorylate and thereby inactivate it in melanoma cells. Here we report that suppression of pleckstrin homology domain and leucine-rich repeat Ser/Thr protein phosphatase 1 (PHLPP1) by DNA methylation promotes Akt activation and has an oncogenic role in melanoma. While it is commonly downregulated, overexpression of PHLPP1 reduces Akt activation and inhibits melanoma cell proliferation in vitro, and retards melanoma growth in a xenograft model. In contrast, knockdown of PHLPP1 increases Akt activation, enhances melanoma cell and melanocyte proliferation, and results in anchorage-independent growth of melanocytes. Suppression of PHLPP1 involves blockade of binding of the transcription factor Sp1 to the PHLPP1 promoter. Collectively, these results suggest that suppression of PHLPP1 by DNA methylation contributes to melanoma development and progression.
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, Newcastle, NSW, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Dong
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, Newcastle, NSW, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Jin
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, Newcastle, NSW, Australia.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Tseng
authors.affiliation: Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Affiliated Hospital of Shanxi Medical University, Taiyuan, China.
authors.forename: C Y
authors.initials: CY
authors.lastname: Wang
authors.affiliation: 1] Melanoma Institute Australia, Sydney, NSW, Australia [2] Discipline of Pathology, The University of Sydney, Sydney, NSW, Australia.
authors.forename: J S
authors.initials: JS
authors.lastname: Wilmott
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Yosufi
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, Newcastle, NSW, Australia.
authors.forename: X G
authors.initials: XG
authors.lastname: Yan
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, Newcastle, NSW, Australia.
authors.forename: C C
authors.initials: CC
authors.lastname: Jiang
authors.affiliation: 1] Melanoma Institute Australia, Sydney, NSW, Australia [2] Discipline of Pathology, The University of Sydney, Sydney, NSW, Australia [3] Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: R A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, Newcastle, NSW, Australia.
authors.forename: X D
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Affiliated Hospital of Shanxi Medical University, Taiyuan, China.
authors.forename: S T
authors.initials: ST
authors.lastname: Guo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D019175:DNA Methylation; D015536:Down-Regulation; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D009687:Nuclear Proteins; D016329:Sp1 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C400601:PHLPP1 protein, human; D010749:Phosphoprotein Phosphatases