Abstract
<div>Abstract<p><b>Purpose:</b> We present here the first report of <i>PID1</i> (<i>P</i>hosphotyrosine <i>I</i>nteraction <i>D</i>omain containing 1; NYGGF4) in cancer. <i>PID1</i> was identified in 2006 as a gene that modulates insulin signaling and mitochondrial function in adipocytes and muscle cells.</p><p><b>Experimental Design and Results:</b> Using four independent medulloblastoma datasets, we show that mean <i>PID1</i> mRNA levels were lower in unfavorable medulloblastomas (groups 3 and 4, and anaplastic histology) compared with favorable medulloblastomas (SHH and WNT groups, and desmoplastic/nodular histology) and with fetal cerebellum. In two large independent glioma datasets, <i>PID1</i> mRNA was lower in glioblastomas (GBM), the most malignant gliomas, compared with other astrocytomas, oligodendrogliomas and nontumor brains. Neural and proneural GBM subtypes had higher <i>PID1</i> mRNA compared with classical and mesenchymal GBM. Importantly, overall survival and radiation-free progression-free survival were longer in medulloblastoma patients whose tumors had higher PID1 mRNA (univariate and multivariate analyses). Higher <i>PID1</i> mRNA also correlated with longer overall survival in patients with glioma and GBM. In cell culture, overexpression of <i>PID1</i> inhibited colony formation in medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and GBM cell lines. Increasing PID1 also increased cell death and apoptosis, inhibited proliferation, induced mitochondrial depolaization, and decreased serum-mediated phosphorylation of AKT and ERK in medulloblastoma, ATRT, and/or GBM cell lines, whereas siRNA to PID1 diminished mitochondrial depolarization.</p><p><b>Conclusions:</b> These data are the first to link PID1 to cancer and suggest that PID1 may have a tumor inhibitory function in these pediatric and adult brain tumors. <i>Clin Cancer Res; 20(4); 827–36. ©2013 AACR</i>.</p></div>
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