title: PI(4,5)P2 5-phosphatase A regulates PI3K/Akt signalling and has a tumour suppressive role in human melanoma.
abstract: Inositol polyphosphate 5-phosphatases can terminate downstream signalling of phosphatidylinositol-3 kinase; however, their biological role in the pathogenesis of cancer is controversial. Here we report that the inositol polyphosphate 5-phosphatase, phosphatidylinositol 4,5-bisphosphate 5-phosphatase, has a tumour suppressive role in melanoma. Although it is commonly downregulated in melanoma, overexpression of phosphatidylinositol 4,5-bisphosphate 5-phosphatase blocks Akt activation, inhibits proliferation and undermines survival of melanoma cells in vitro, and retards melanoma growth in a xenograft model. In contrast, knockdown of phosphatidylinositol 4,5-bisphosphate 5-phosphatase results in increased proliferation and anchorage-independent growth of melanocytes. Although DNA copy number loss is responsible for downregulation of phosphatidylinositol 4,5-bisphosphate 5-phosphatase in a proportion of melanomas, histone hypoacetylation mediated by histone deacetylases HDAC2 and HDAC3 through binding to the transcription factor Sp1 at the PIB5PA gene promoter appears to be another commonly involved mechanism. Collectively, these results establish the tumour suppressive role of phosphatidylinositol 4,5-bisphosphate 5-phosphatase and reveal mechanisms involved in its downregulation in melanoma.
authors: School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales 2308, Australia.
authors: Yan
authors: Y
authors: Ye
authors: Lei
authors: L
authors: Jin
authors: James S
authors: JS
authors: Wilmott
authors: Wang Lai
authors: WL
authors: Hu
authors: Benafsha
authors: B
authors: Yosufi
authors: Rick F
authors: RF
authors: Thorne
authors: Tao
authors: T
authors: Liu
authors: Helen
authors: H
authors: Rizos
authors: Xu Guang
authors: XG
authors: Yan
authors: Li
authors: L
authors: Dong
authors: Kwang Hong
authors: KH
authors: Tay
authors: Hsin-Yi
authors: HY
authors: Tseng
authors: Su Tang
authors: ST
authors: Guo
authors: Charles E
authors: CE
authors: de Bock
authors: Chen Chen
authors: CC
authors: Jiang
authors: Chun Yan
authors: CY
authors: Wang
authors: Mian
authors: M
authors: Wu
authors: Lin Jie
authors: LJ
authors: Zhang
authors: Peter
authors: P
authors: Hersey
authors: Richard A
authors: RA
authors: Scolyer
authors: Xu Dong
authors: XD
authors: Zhang
mesh_terms: D000107:Acetylation; D000818:Animals; D002448:Cell Adhesion; D002457:Cell Extracts; D049109:Cell Proliferation; D002470:Cell Survival; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D015894:Genome, Human / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008544:Melanocytes / Q000201:enzymology / Q000473:pathology; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic; D023041:Xenograft Model Antitumor Assays; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D002457:Cell Extracts; D006657:Histones; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D000099182:Phosphoinositide 5-Phosphatases; C494929:PTEN protein, human