Promotion of glioblastoma cell motility by enhancer of zeste homolog 2 (EZH2) is mediated by AXL receptor kinase.
Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the Polycomb-repressive complex 2 (PRC2) that epigenetically silences gene transcription through histone H3 lysine trimethylation (H3K27me3). EZH2 has been implicated in stem cell maintenance and is overexpressed in hematological and solid malignancie`s including malignant glioma. EZH2 is thought to promote tumor progression by silencing tumor suppressor genes. Hence pharmacological disruption of the PRC2 is an attractive therapeutic strategy for cancer treatment. Here we show that EZH2 is expressed in human glioma and correlates with malignancy. Silencing of EZH2 reduced glioma cell proliferation and invasiveness. While we did not observe induction of cell cycle-associated tumor suppressor genes by silencing or pharmacological inhibition of EZH2, microarray analyses demonstrated a strong transcriptional reduction of the AXL receptor kinase. Neither histone nor DNA methylation appeared to be involved in the positive regulation of AXL by EZH2. Silencing AXL mimicked the antiinvasive effects of EZH2 knockdown. Finally, AXL expression is found in human gliomas with high EZH2 expression. Collectively these data suggest that EZH2 drives glioma invasiveness via transcriptional control of AXL independent of histone or DNA methylation.
Department of Neurooncology, University Hospital Heidelberg, Heidelberg, Germany.
Martina
M
Ott
Ulrike M
UM
Litzenburger
Felix
F
Sahm
Katharina J
KJ
Rauschenbach
Ruxandra
R
Tudoran
Christian
C
Hartmann
Victor E
VE
Marquez
Andreas
A
von Deimling
Wolfgang
W
Wick
Michael
M
Platten
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D002471:Cell Transformation, Neoplastic; D019175:DNA Methylation; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D005910:Glioma / Q000235:genetics; D006801:Humans; D009361:Neoplasm Invasiveness; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D000094963:Axl Receptor Tyrosine Kinase
D011518:Proto-Oncogene Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human