title: Differential expression of the tumor suppressor A-kinase anchor protein 12 in human diffuse and pilocytic astrocytomas is regulated by promoter methylation.
abstract: The scaffold protein A-kinase anchor protein 12 (AKAP12) exerts tumor suppressor activity and is downregulated in several tumor entities. We characterized AKAP12 expression and regulation in astrocytomas, including pilocytic and diffusely infiltrating astrocytomas. We examined 194 human gliomas and 23 normal brain white matter samples by immunohistochemistry or immunoblotting for AKAP12 expression. We further performed quantitative methylation analysis of the AKAP12 promoter by MassARRAY® of normal brain, World Health Organization (WHO) grade I to IV astrocytomas, and glioma cell lines. Our results show that AKAP12 is expressed in a perivascular distribution in normal CNS, strongly upregulated in tumor cells in pilocytic astrocytomas, and weakly expressed in diffuse astrocytomas of WHO grade II to IV. Methylation analyses revealed specific hypermethylation of AKAP12α promoter in WHO grade II to IV astrocytomas. Restoration experiments using 5-aza-2'-deoxycytidine in primary glioblastoma cells decreased AKAP12α promoter methylation and markedly increased AKAP12α mRNA levels. In summary, we demonstrate that AKAP12 is differentially expressed in human astrocytomas showing high expression in pilocytic but low expression in diffuse astrocytomas of all WHO-grades. Our results further indicate that epigenetic mechanisms are involved in silencing AKAP12 in diffuse astrocytomas; however, a tumor suppressive role of AKAP12 in distinct astrocytoma subtypes remains to be determined.
authors.affiliation: From the Institute of Pathology, University Hospital Heidelberg (BG, MR, WW, PS); Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ) (CRS, LG, CD, PS, OP, CP); Department of Neuropathology, University of Heidelberg (DC); Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) (DC, WW); and Department of Neuroradiology, University of Heidelberg (MNV), Heidelberg; Edinger Institute, University Hospital Frankfurt a.M., Frankfurt (CZ, JZ, PNH, MM); and Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg (BC); and Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg (WW), Heidelberg, Germany; Department of Neurology, University Hospital Zurich, Zurich, Switzerland (MW); and Department of Neuropathology, Institute of Pathology and Neuropathology, Eberhard-Karls-University of Tübingen, Tübingen (RM, JS); and Department of Sports Medicine, Rehabilitation and Disease Prevention, Johannes Gutenberg University, Mainz (PS), Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Goeppert
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Schmidt
authors.forename: Lea
authors.initials: L
authors.lastname: Geiselhart
authors.forename: Céline
authors.initials: C
authors.lastname: Dutruel
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.forename: Marcus
authors.initials: M
authors.lastname: Renner
authors.forename: Monika Nadja
authors.initials: MN
authors.lastname: Vogel
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zachskorn
authors.forename: Jenny
authors.initials: J
authors.lastname: Zinke
authors.forename: Benito
authors.initials: B
authors.lastname: Campos
authors.forename: Peter
authors.initials: P
authors.lastname: Schmezer
authors.forename: Odilia
authors.initials: O
authors.lastname: Popanda
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Richard
authors.initials: R
authors.lastname: Meyermann
authors.forename: Jens
authors.initials: J
authors.lastname: Schittenhelm
authors.forename: Patrick Nikolaus
authors.initials: PN
authors.lastname: Harter
authors.forename: Perikles
authors.initials: P
authors.lastname: Simon
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011401:Promoter Regions, Genetic; D015854:Up-Regulation
chemical_list: D054758:A Kinase Anchor Proteins; C491162:AKAP12 protein, human; D018797:Cell Cycle Proteins