MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B

Cancer Cell. 2016 Jan 11;29(1):49-60. doi: 10.1016/j.ccell.2015.12.005.

Abstract

The hypoxic tumor microenvironment serves as a niche for maintaining the glioma-initiating cells (GICs) that are critical for glioblastoma (GBM) occurrence and recurrence. Here, we report that hypoxia-induced miR-215 is vital for reprograming GICs to fit the hypoxic microenvironment via suppressing the expression of an epigenetic regulator KDM1B and modulating activities of multiple pathways. Interestingly, biogenesis of miR-215 and several miRNAs is accelerated post-transcriptionally by hypoxia-inducible factors (HIFs) through HIF-Drosha interaction. Moreover, miR-215 expression correlates inversely with KDM1B while correlating positively with HIF1α and GBM progression in patients. These findings reveal a direct role of HIF in regulating miRNA biogenesis and consequently activating the miR-215-KDM1B-mediated signaling required for GIC adaptation to hypoxia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology
  • Cell Hypoxia
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / genetics*
  • Glioma / genetics*
  • Humans
  • Mice, Nude
  • MicroRNAs / genetics*
  • Neoplasm Recurrence, Local / genetics
  • Oxidoreductases, N-Demethylating / genetics*
  • Tumor Microenvironment / genetics*

Substances

  • MIRN215 microRNA, human
  • MIRN215 microRNA, mouse
  • MicroRNAs
  • Oxidoreductases, N-Demethylating
  • kdm1b protein, mouse