Epigenetic downregulation of mitogen-activated protein kinase phosphatase MKP-2 relieves its growth suppressive activity in glioma cells.
Critical tumor suppression pathways in brain tumors have yet to be fully defined. Along with mutational analyses, genome-wide epigenetic investigations may reveal novel suppressor elements. Using differential methylation hybridization, we identified a CpG-rich region of the promoter of the dual-specificity mitogen-activated protein kinase phosphatase-2 gene (DUSP4/MKP-2) that is hypermethylated in gliomas. In 83 astrocytic gliomas and 5 glioma cell lines examined, hypermethylation of the MKP-2 promoter was found to occur relatively more frequently in diffuse or anaplastic astrocytomas and secondary glioblastomas relative to primary glioblastomas. MKP-2 hypermethylation was associated with mutations in TP53 and IDH1, exclusive of EGFR amplification, and with prolonged survival of patients with primary glioblastoma. Expression analysis established that promoter hypermethylation correlated with reduced expression of MKP-2 mRNA and protein. Consistent with a regulatory role, reversing promoter hypermethylation by treating cells with 5-aza-2'-deoxycytidine increased MKP-2 mRNA levels. Furthermore, we found that glioblastoma cell growth was inhibited by overexpression of exogenous MKP-2. Our findings reveal MKP-2 as a common epigenetically silenced gene in glioma, the inactivation of which may play a significant role in glioma development.
Waha
Anke
A
Department of Neuropathology, University of Bonn, D-53105 Bonn, Germany.
Felsberg
Jörg
J
Hartmann
Wolfgang
W
von dem Knesebeck
Anna
A
Mikeska
Thomas
T
Joos
Stefan
S
Wolter
Marietta
M
Koch
Arend
A
Yan
Pearlly S
PS
Endl
Elmar
E
Wiestler
Otmar D
OD
Reifenberger
Guido
G
Pietsch
Torsten
T
Waha
Andreas
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D015536:Down-Regulation / Q000502:physiology; D054637:Dual-Specificity Phosphatases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D020868:Gene Silencing / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
D054639:Mitogen-Activated Protein Kinase Phosphatases; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases