MiR-128 controls the activity of Polycomb Repressor Complexes 1 and 2 in Neural Stem Cells: Implications of its loss in gliomagenesis.
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.
Molecular Biology, Oncology, miR-128, glioblastoma, neural stem cells, Polycomb, BMI1, SUZ12
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