TY - JOUR
T1 - Differential expression of the tumor suppressor A-kinase anchor protein 12 in human diffuse and pilocytic astrocytomas is regulated by promoter methylation
AU - Goeppert, Benjamin
AU - Schmidt, Christopher R.
AU - Geiselhart, Lea
AU - Dutruel, Céline
AU - Capper, David
AU - Renner, Marcus
AU - Vogel, Monika Nadja
AU - Zachskorn, Cornelia
AU - Zinke, Jenny
AU - Campos, Benito
AU - Schmezer, Peter
AU - Popanda, Odilia
AU - Wick, Wolfgang
AU - Weller, Michael
AU - Meyermann, Richard
AU - Schittenhelm, Jens
AU - Harter, Patrick Nikolaus
AU - Simon, Perikles
AU - Weichert, Wilko
AU - Schirmacher, Peter
AU - Plass, Christoph
AU - Mittelbronn, Michel
PY - 2013/10
Y1 - 2013/10
N2 - 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.
AB - 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.
KW - AKAP12
KW - Astrocytoma
KW - Gravin
KW - Promoter methylation
KW - SSeCKS
UR - http://www.scopus.com/inward/record.url?scp=84885038430&partnerID=8YFLogxK
U2 - 10.1097/NEN.0b013e3182a59a88
DO - 10.1097/NEN.0b013e3182a59a88
M3 - Article
C2 - 24042196
AN - SCOPUS:84885038430
SN - 0022-3069
VL - 72
SP - 933
EP - 941
JO - Journal of Neuropathology and Experimental Neurology
JF - Journal of Neuropathology and Experimental Neurology
IS - 10
ER -