A role for the transcription factor HEY1 in glioblastoma.
Abstract Glioblastoma multiforme (GBM), the highest-grade glioma, is the most frequent tumour of the brain with a very poor prognosis and limited therapeutic options. Although little is known about the molecular mechanisms that underlie glioblastoma formation, a number of signal transduction routes, such as the Notch and Ras signalling pathways, seem to play an important role in the formation of GBM. In the present study, we show by in situ hybridization on primary tumour material that the transcription factor HEY1, a target of the Notch signalling pathway, is specifically up-regulated in glioma and that expression of HEY1 in GBM correlates with tumour-grade and survival. In addition, we show by chromatin immunoprecipitations, luciferase assays and Northern blot experiments that HEY1 is a bona fide target of the E2F family of transcription factors, connecting the Ras and Notch signalling pathways. Finally, we show that ectopic expression of HEY1 induces cell proliferation in neural stem cells, while depletion of HEY1 by RNA interference reduces proliferation of glioblastoma cells in tissue culture. Together, these data imply a role for HEY1 in the progression of GBM, and therefore we propose that HEY1 may be a therapeutic target for glioblastoma patients. Moreover, HEY1 may represent a molecular marker to distinguish GBM patients with a longer survival prognosis from those at high risk.
Hulleman
Esther
E
European Institute of Oncology, Via Ripamonti, Milan, Italy.
Quarto
Micaela
M
Vernell
Richard
R
Masserdotti
Giacomo
G
Colli
Elena
E
Kros
Johan M
JM
Levi
Daniel
D
Gaetani
Paolo
P
Tunici
Patrizia
P
Finocchiaro
Gaetano
G
Baena
Riccardo Rodriguez Y
RR
Capra
Maria
M
Helin
Kristian
K
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D018450:Disease Progression; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D034622:RNA Interference; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D046888:Tissue Array Analysis
D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D050684:E2F Transcription Factors; D051880:Receptors, Notch; C485631:HEY1 protein, human