MiR-128 controls the activity of Polycomb Repressor Complexes 1 and 2 in Neural Stem Cells: Implications of its loss in gliomagenesis.
type: CreativeWork
description: The Polycomb Repressor Complex (PRC) is an epigenetic regulator of transcription whose action is mediated by two protein complexes, PRC1 and PRC2. PRC activity normally plays a key role in stem cell maintenance, but it is oncogenic in glioblastoma where it is involved in cancer stem cell maintenance and radio-resistance. Here we show that miR-128 directly targets the mRNA of BMI1 and SUZ12, key components of PRC1 and PRC2, respectively. This blocks the partially redundant functions of PRC1/PRC2, thereby significantly reducing PRC activity and its associated histone modifications. MiR-128 and SUZ12/BMI1 show opposite expression in human glioblastomas versus normal brain and in glioma stem-like versus neural stem cells. MiR-128 expression is significantly reduced in the brain of young mice genetically engineered to develop glioblastomas before tumor development, as compared to the elevated expression of miR-128 in the brain of wild-type mice. This suggests that loss of miR-128 expression in brain is an early event in gliomagenesis. Moreover, knock-down of miR-128 expression in non-malignant mouse and human neural stem cells led to elevated expression of PRC components and increased clonogenicity, suggesting that miR-128 is an important suppressor of PRC activity and its absence is an early event in gliomagenesis. Finally, miR-128 renders glioma initiating cells less radio-resistant by preventing the radiation-induced expression of both PRC components thus impairing the DNA repair after radiation-induced double strand DNA breaks.Taken together our results suggest an important role for the loss of miR-128 in the pathogenesis of glioblastoma and its potential for a future therapeutic use.
abstract: The Polycomb Repressor Complex (PRC) is an epigenetic regulator of transcription whose action is mediated by two protein complexes, PRC1 and PRC2. PRC activity normally plays a key role in stem cell maintenance, but it is oncogenic in glioblastoma where it is involved in cancer stem cell maintenance and radio-resistance. Here we show that miR-128 directly targets the mRNA of BMI1 and SUZ12, key components of PRC1 and PRC2, respectively. This blocks the partially redundant functions of PRC1/PRC2, thereby significantly reducing PRC activity and its associated histone modifications. MiR-128 and SUZ12/BMI1 show opposite expression in human glioblastomas versus normal brain and in glioma stem-like versus neural stem cells. MiR-128 expression is significantly reduced in the brain of young mice genetically engineered to develop glioblastomas before tumor development, as compared to the elevated expression of miR-128 in the brain of wild-type mice. This suggests that loss of miR-128 expression in brain is an early event in gliomagenesis. Moreover, knock-down of miR-128 expression in non-malignant mouse and human neural stem cells led to elevated expression of PRC components and increased clonogenicity, suggesting that miR-128 is an important suppressor of PRC activity and its absence is an early event in gliomagenesis. Finally, miR-128 renders glioma initiating cells less radio-resistant by preventing the radiation-induced expression of both PRC components thus impairing the DNA repair after radiation-induced double strand DNA breaks.Taken together our results suggest an important role for the loss of miR-128 in the pathogenesis of glioblastoma and its potential for a future therapeutic use.
author: Peruzzi, Pierpaolo
language: English
keywords: Molecular Biology, Oncology, miR-128, glioblastoma, neural stem cells, Polycomb, BMI1, SUZ12
date published: 2013-08-09
date modified: 2026-07-24T03:37:46Z
provider: OhioLINK
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: The Ohio State University