PI(4,5)P2 5-phosphatase A regulates PI3K/Akt signalling and has a tumour suppressive role in human melanoma

Yan Ye, Lei Jin, James S. Wilmott, Wang Lai Hu, Benafsha Yosufi, Rick F. Thorne, Tao Liu, Helen Rizos, Xu Guang Yan, Li Dong, Kwang Hong Tay, Hsin-Yi Tseng, Su Tang Guo, Charles E. de Bock, Chen Chen Jiang, Chun Yan Wang, Mian Wu, Lin Jie Zhang, Peter Hersey, Richard A. Scolyer and Xu Dong Zhang ()
Additional contact information
Yan Ye: School of Medicine and Public Health, University of Newcastle
Lei Jin: Melanoma Institute Australia
James S. Wilmott: Melanoma Institute Australia
Wang Lai Hu: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China
Benafsha Yosufi: Melanoma Institute Australia
Rick F. Thorne: Cancer Research Unit, University of Newcastle
Tao Liu: Children’s Cancer Institute Australia for Medical Research, University of New South Wales
Helen Rizos: Melanoma Institute Australia
Xu Guang Yan: Cancer Research Unit, University of Newcastle
Li Dong: School of Medicine and Public Health, University of Newcastle
Kwang Hong Tay: School of Medicine and Public Health, University of Newcastle
Hsin-Yi Tseng: School of Medicine and Public Health, University of Newcastle
Su Tang Guo: Shanxi Cancer Hospital and Institute
Charles E. de Bock: Cancer Research Unit, University of Newcastle
Chen Chen Jiang: School of Medicine and Public Health, University of Newcastle
Chun Yan Wang: Shanxi Cancer Hospital and Institute
Mian Wu: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China
Lin Jie Zhang: Anhui Medical University
Peter Hersey: Melanoma Institute Australia
Richard A. Scolyer: Melanoma Institute Australia
Xu Dong Zhang: School of Medicine and Public Health, University of Newcastle

Nature Communications, 2013, vol. 4, issue 1, 1-15

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2489

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