title: Analysis of EZH2: micro-RNA network in low and high grade astrocytic tumors.
abstract: Enhancer of Zeste homologue2 (EZH2) is an epigenetic regulator that functions as oncogene in astrocytic tumors, however, EZH2 regulation remains little studied. In this study, we measured EZH2 levels in low (Gr-II,DA) and high grade (Gr-IV,GBM) astrocytic tumors and found significant increased EZH2 transcript level with grade(median DA-8.5, GBM-28.9).However, a different trend was reflected in protein levels, with GBMs showing high EZH2 LI(median-26.5) compared to DA (median 0.3). This difference in correlation of EZH2 protein and RNA levels suggested post-transcriptional regulation of EZH2, likely mediated by miRNAs. We selected eleven miRNAs that strongly predicted to target EZH2 and measured their expression. Three miRNAs (miR-26a-5p,miR27a-3p and miR-498) showed significant correlation with EZH2 protein, suggesting them as regulators of EZH2, however miR-26a-5p levels decreased with grade. ChIP analyses revealed H3K27me3 modifications in miR-26a promoter suggesting feedback loop between EZH2 and miR26a. We further measured six downstream miRNA targets of EZH2 and found significant downregulation of four (miR-181a/b and 200b/c) in GBM. Interestingly, EZH2 associated miRNAs were predicted to target 25 genes in glioma-pathway, suggesting their role in tumor formation or progression. Collectively, our work suggests EZH2 and its miRNA interactors may serve as promising biomarkers for progression of astrocytic tumors and may offer novel therapeutic strategies.
authors.affiliation: Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
authors.forename: Suvendu
authors.initials: S
authors.lastname: Purkait
authors.affiliation: Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India.
authors.forename: Sonam
authors.initials: S
authors.lastname: Takkar
authors.affiliation: Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
authors.forename: Prit Benny
authors.initials: PB
authors.lastname: Malgulwar
authors.affiliation: Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
authors.forename: Anupam
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Pathak
authors.affiliation: Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
authors.forename: Vaishali
authors.initials: V
authors.lastname: Suri
authors.affiliation: Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
authors.forename: Mehar C
authors.initials: MC
authors.lastname: Sharma
authors.affiliation: Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, 110029, India.
authors.forename: Ashish
authors.initials: A
authors.lastname: Suri
authors.affiliation: Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, 110029, India.
authors.forename: Shashank Sharad
authors.initials: SS
authors.lastname: Kale
authors.affiliation: Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India. ritu@dbeb.iitd.ac.in.
authors.forename: Ritu
authors.initials: R
authors.lastname: Kulshreshtha
authors.affiliation: Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India. sarkar.chitra@gmail.com.
authors.forename: Chitra
authors.initials: C
authors.lastname: Sarkar
mesh_terms: D000328:Adult; D000368:Aged; D001254:Astrocytoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D004843:Epistasis, Genetic; D005260:Female; D015870:Gene Expression / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology*; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D055815:Young Adult
chemical_list: D035683:MicroRNAs; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein
keywords: Astrocytic tumors; EZH2; Glioblastoma; MicroRNAs