Methylation regulates HEY1 expression in glioblastoma
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Andrew J. Tsung1,2,3,*, Maheedhara R. Guda1,*, Swapna Asuthkar1,*, Collin M. Labak1,*, Ian J. Purvis1, Yining Lu1, Neha Jain1, Sarah E. Bach4, Durbaka V.R. Prasad5 and Kiran K. Velpula1,2,5
1Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA
2Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL, USA
3Illinois Neurological Institute, Peoria, IL, USA
4Department of Pathology, Peoria, IL, USA
5Department of Microbiology, Yogi Vemana University, Kadapa, India
*These authors contributed equally to this work
Kiran K. Velpula, email: [email protected]
Keywords: glioblastoma, methylation, p53, proliferation, DNMT1
Received: October 04, 2016 Accepted: May 01, 2017 Published: May 16, 2017
Glioblastoma (GBM) remains one of the most lethal and difficult-to-treat cancers of the central nervous system. The poor prognosis in GBM patients is due in part to its resistance to available treatments, which calls for identifying novel molecular therapeutic targets. In this study, we identified a mediator of Notch signaling, HEY1, whose methylation status contributes to the pathogenesis of GBM. Datamining studies, immunohistochemistry and immunoblot analysis showed that HEY1 is highly expressed in GBM patient specimens. Since methylation status of HEY1 may control its expression, we conducted bisulphite sequencing on patient samples and found that the HEY1 promoter region was hypermethylated in normal brain when compared to GBM specimens. Treatment on 4910 and 5310 xenograft cell lines with sodium butyrate (NaB) significantly decreased HEY1 expression with a concomitant increase in DNMT1 expression, confirming that promoter methylation may regulate HEY1 expression in GBM. NaB treatment also induced apoptosis of GBM cells as measured by flow cytometric analysis. Further, silencing of HEY1 reduced invasion, migration and proliferation in 4910 and 5310 cells. Furthermore, immunoblot and q-PCR analysis showed the existence of a potential positive regulatory loop between HEY1 and p53. Additionally, transcription factor interaction array with HEY1 recombinant protein predicted a correlation with p53 and provided various bonafide targets of HEY1. Collectively, these studies suggest HEY1 may be an important predictive marker for GBM and potential target for future GBM therapy.
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