Editors' ChoiceCancer

Hypoxia micromanages glioma

Sci. Signal.  19 Jan 2016:
Vol. 9, Issue 411, pp. ec11
DOI: 10.1126/scisignal.aaf2508

Glioblastoma (GBM) is an aggressive brain cancer that is often characterized by a hypoxic microenvironment. Hypoxia-inducible factors (HIFs) transcriptionally promote multiple processes associated with GBM progression. Hu et al. found that hypoxia-induced HIF1α in GBM increased the production of a microRNA (miRNA) that drove the proliferation of glioma-initiating cells (GICs), a subpopulation of cells that may promote the growth and recurrence of GBM. The abundance of various miRNAs was increased by hypoxia, but only the functional blocking of miR-215 decreased the proliferation of cultured patient tumor–derived GICs in intracranial xenografts in mice. The amount of mature miR-215 and pre-miR-215, but not that of pri-miR-215, was increased in GICs cultured under hypoxic conditions, suggesting that the production of miR-215 was enhanced at a posttranscriptional step in the miRNA biogenesis pathway. However, the abundance of the Drosha and Dicer complexes that mediate this step was not increased by hypoxia. HIF1α, the abundance of which was increased in hypoxic GICs, interacted with the Drosha complex on pri-miR-215, and silencing HIF1α prevented the hypoxia-induced increase in the amount of miR-215 in GICs. Microarray and reporter analyses in GICs revealed that miR-215 targets and silences the mRNA encoding the histone demethylase KDM1B. Knocking down KDM1B in GICs increased neurosphere formation and the expression of genes associated with glucose metabolism in GIC cultures, and endothelial cells cultured in medium conditioned by KDM1B-deficient GICs exhibited increased migration. Decreased abundance of KDM1B in GBM patient tumors correlated with increased expression of HIF1A and miR-215 and with poor patient survival. The findings identify a miRNA biogenesis-targeted pathway through which hypoxia promotes GBM growth.

J. Hu, T. Sun, H. Wang, Z. Chen, S. Wang, L. Yuan, T. Liu, H.-R. Li, P. Wang, Y. Feng, Q. Wang, R. E. McLendon, A. H. Friedman, S. T. Keir, D. D. Bigner, J. Rathmell, X.-d. Fu, Q.-J. Li, H. Wang, X.-F. Wang, MiR-215 is induced post-transcriptionally via HIF-Drosha complex and mediates glioma-initiating cell adaptation to hypoxia by targeting KDM1B. Cancer Cell 29, 49–60 (2016). [PubMed]