title: Expression of podoplanin in human astrocytic brain tumors is controlled by the PI3K-AKT-AP-1 signaling pathway and promoter methylation.
abstract: Recently, we found strong overexpression of the mucin-type glycoprotein podoplanin (PDPN) in human astrocytic brain tumors, specifically in primary glioblastoma multiforme (GB). In the current study, we show an inverse correlation between PDPN expression and PTEN levels in primary human GB and glioma cell lines, and we report elevated PDPN protein levels in the subventricular zone of brain tissue sections of PTEN-deficient mice. In human glioma cells lacking functional PTEN, reintroduction of wild-type PTEN, inhibition of the PTEN downstream target protein kinase B/AKT, or interference with transcription factor AP-1 function resulted in efficient downregulation of PDPN expression. In addition, we observed hypoxia-dependent PDPN transcriptional control and demonstrated that PDPN expression is subject to negative transcriptional regulation by promoter methylation in human GB and in glioma cell lines. Treatment of PTEN-negative glioma cells with demethylating agents induced expression of PDPN. Together, our findings show that increased PDPN expression in human GB is caused by loss of PTEN function and activation of the PI3K-AKT-AP-1 signaling pathway, accompanied by epigenetic regulation of PDPN promoter activity. Silencing of PDPN expression leads to reduced proliferation and migration of glioma cells, suggesting a functional role of PDPN in glioma progression and malignancy. Thus, specific targeting of PDPN expression and/or function could be a promising strategy for the treatment of patients with primary GB.
authors.affiliation: Divisions of Signal Transduction and Growth Control, DKFZ/ZMBH Alliance, Heidelberg, Germany. h.peterziel@dkfz.de
authors.forename: Heike
authors.initials: H
authors.lastname: Peterziel
authors.forename: Julia
authors.initials: J
authors.lastname: Müller
authors.forename: Andreas
authors.initials: A
authors.lastname: Danner
authors.forename: Sebastian
authors.initials: S
authors.lastname: Barbus
authors.forename: Hai-Kun
authors.initials: HK
authors.lastname: Liu
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlwimmer
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
authors.forename: Jochen
authors.initials: J
authors.lastname: Hess
authors.forename: Peter
authors.initials: P
authors.lastname: Angel
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D005910:Glioma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D000098853:Podoplanin
chemical_list: D008562:Membrane Glycoproteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018808:Transcription Factor AP-1; C117468:PDPN protein, human; D000098853:Podoplanin; C494929:PTEN protein, human