Evaluation of gene expression in notch pathway and their epigenetic status from human glioma samples

Abstract

Glioblastoma multiforme is the most common and highly malignant brain tumor with a poor prognosis of less than a year despite advance treatment strategies. This could be due to lack of efficient diagnostic biomarkers and targeted therapy. Thus, it is essential to discover molecular mechanisms underlying disease by identifying genetic and epigenetic alterations in important signal transduction pathways involved in tumorigenesis. Notch pathway is one such developmental cell signaling pathway governing cell fate decisions. Dysregulated Notch pathway is found to have an important role in the development of several cancers. Additionally, DNA methylation in promoter regions of vital cell signaling pathway genes have been linked to altered gene expression in cancer. Thus, aberrant gene expression and hypermethylation hold great promise as biomarkers for early detection and effective drug targets. Various herbal products having anticancer properties are being used in adjuvant therapy that is nontoxic and affordable. Bacopa monnieri is a herbaceous plant which has been used in Ayurveda against various brain related conditions because of its neuroprotective properties. Also, its anticancer properties have shown to be promising in treating cancers. newline newlineThis study aimed to asses the expression of Notch signaling pathway genes in Glioblastoma patient samples to identify any dysregulated genes and to verify if the aberrant expression is regulated by promoter methylation with an aim to identify biomarkers that can improve diagnosis and therapeutic strategies. Furthermore, an attempt was made to assess the anticancer properties of Bacoside A, which is a component of Bacopa monnieri on U-87 MG cell line and determine its influence on expression of Notch pathway genes. newline newlineThe present study revealed aberrant expression of Notch genes in Glioblastoma compared to normal brain. DNA methylation observerd in Notch gene promoters suggests a possibility of epigenetic silencing. Bacoside A showed considerable cytotoxicity on Glioblastoma cell line causing cell cycle arrest and apoptosis via regulation of Notch genes. This study for the first time provides gene expression and DNA methylation profiles of Notch pathway genes in Glioblastoma. The results show aberrant expression of Notch genes whose expression may be regulated by epigenetic mechanisms suggesting them as biomarkers that could be used together with histopathological observation to improve diagnosis and treatment. Further more, these data suggest that Bacoside A could have a potential anticancer activity inducing cell cycle arrest and apoptosis via Notch signaling pathway in Glioblastoma cell line U-87 MG. newline newline