School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales 2308, Australia.
Nat Commun. 2013;4:1508. doi: 10.1038/ncomms2489.
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.
肌醇多磷酸 5-磷酸酶可以终止磷脂酰肌醇-3-激酶的下游信号转导；然而，它们在癌症发病机制中的生物学作用存在争议。在这里，我们报告说，肌醇多磷酸 5-磷酸酶，即磷脂酰肌醇 4,5-二磷酸 5-磷酸酶，在黑色素瘤中具有肿瘤抑制作用。尽管它在黑色素瘤中通常下调，但过表达磷脂酰肌醇 4,5-二磷酸 5-磷酸酶会阻断 Akt 激活，抑制黑色素瘤细胞的增殖并破坏其体外存活能力，并在异种移植模型中延缓黑色素瘤的生长。相比之下，敲低磷脂酰肌醇 4,5-二磷酸 5-磷酸酶会导致黑素细胞增殖和非依赖性生长增加。虽然在一部分黑色素瘤中，DNA 拷贝数的丢失导致磷脂酰肌醇 4,5-二磷酸 5-磷酸酶的下调，但通过与转录因子 Sp1 结合，组蛋白去乙酰化酶 HDAC2 和 HDAC3 介导的组蛋白乙酰化似乎是另一种常见的涉及机制。总之，这些结果确立了磷脂酰肌醇 4,5-二磷酸 5-磷酸酶的肿瘤抑制作用，并揭示了其在黑色素瘤中下调的相关机制。
