PPARα Regulates the Proliferation of Human Glioma Cells through miR-214 and E2F2

Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a member of the nuclear hormone receptor superfamily and functions as a transcription factor. Previous work showed that PPAR alpha plays multiple roles in lipid metabolism in tissues such as cardiac and skeletal muscle, liver, and adipose tissue. Recent studies have discovered additional roles for PPARa alpha in cell proliferation and metabolism, as well as tumor progression. PPAR alpha is aberrantly expressed in various cancers, and activated PPAR alpha inhibits the proliferation of some tumor cells. However, there have been no studies of PPAR alpha in human gliomas. Here, we show that PPAR alpha is expressed at lower levels in anaplastic gliomas and glioblastoma multiforme (GBM) tissue compared with low-grade gliomas tissue, and low expression is associated with poor patient prognosis. PPAR alpha activates transcription of dynamin-3 opposite strand (DNMO3os), which encodes a cluster of miR-214, miR-199a-3p, and miR-199a-5p microRNAs. Of these, miR-214 is transcribed at particularly high levels. PPAR alpha-induced miR-214 expression causes downregulation of its target E2F2. Finally, miR214 overexpression inhibits glioma cell growth in vitro and in vivo by inducing cell cycle arrest in G0/G1. Collectively, these data uncover a novel role for a PPAR alpha-miR-214-E2F2 pathway in controlling glioma cell proliferation.