PID1 (NYGGF4), a New Growth-Inhibitory Gene in Embryonal Brain Tumors and Gliomas

Abstract

Purpose We present here the first report of PID1 (Phosphotyrosine Interaction Domain containing 1; NYGGF4) in cancer. PID1 was identified in 2006 as a gene that modulates insulin signaling and mitochondrial function in adipocytes and muscle cells. Experimental Design and Results Using four independent medulloblastoma datasets, we show that mean PID1 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 PID1 mRNA was lower in glioblastomas (GBMs), the most malignant gliomas, compared to other astrocytomas, oligodendrogliomas and non-tumor brains. Neural and proneural GBM subtypes had higher PID1 mRNA compared to classical and mesenchymal GBM. Importantly, overall survival and radiation-free progression-free survival were longer in medulloblastoma patients with higher PID1 mRNA (univariate and multivariate analyses). Higher PID1 mRNA also correlated with longer overall survival in glioma and GBM patients. In cell culture, overexpression of PID1 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 depolarization, and decreased serum-mediated phosphorylation of AKT and ERK in medulloblastoma, ATRT and/or GBM cell lines, whereas siRNA to PID1 diminished mitochondrial depolarization. Conclusions 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.

The Effect of Different Case Definitions of Current Smoking on the Discovery of Smoking-Related Blood Gene Expression Signatures in Chronic Obstructive Pulmonary Disease

“…36 Its genetic variants have been associated with autism. 37 Phosphotyrosine interaction domain containing one (PID1) function as a growth-inhibitory gene in brain tumors 38 and is a potent intracellular inhibitor of the insulin signaling pathway during obesity in humans and mice. 39 Fucosidase, alpha-L-1, tissue (FUCA1) is a liposomal enzyme that degrades a variety of fucosecontaining fucoglycoconjugates and has been proposed as a promising tumor marker in the diagnosis 40 and prognosis 41 of hepatocellular carcinoma.…”

PID1 increases chemotherapy-induced apoptosis in medulloblastoma and glioblastoma cells in a manner that involves NFκB

“…Anti-PID1 rabbit polyclonal antibody (Sigma-Aldrich catalog #HPA036103) was used at 1:1,000 as described 7 . Anti-GAPDH mouse monoclonal (1:20,000) and anti-ERK rabbit antibody (1:1000) were from Santa Cruz Biotechnology, CA.…”

“…PID1 has been linked to obesity, insulin resistance, Alzheimer’s disease and cancer 1, 5–7 . PID1 is mostly known for its inhibition of insulin receptor signaling, impairment of mitochondrial function and binding through its phosphotyrosine binding (PTB) domain to the second NPXY motif in the cytoplasmic tail of the low density lipoprotein receptor-related protein 1 (LRP1) 1–5, 8–12 .…”

“…PID1 decreased proliferation, induced apoptosis, impaired mitochondrial membrane potential, and inhibited phosphorylation of AKT and ERK in medulloblastoma and glioblastoma (GBM) cell lines 7 . Clinically, levels of PID1 mRNA in medulloblastoma and glioma tumors directly correlate with patient survival 7 .…”

Inhibition of PID1/NYGGF4/PCLI1 gene expression highlights its role in the early events of the cell cycle in NIH3T3 fibroblasts

“…More recently, PCLI1 was reported as a potential tumor suppressor gene in brain tumors, since its mRNA levels were found to be lower in aggressive medulloblastomas and glioblastomas, compared to their more favorable counterparts. Overexpression of PCLI1 in cultured brain tumor cell lines correlated with increased depolarization of mitochondrial membrane potential, reduced proliferation, increased cell death, and inhibition of serum-mediated phosphorylation of AKT and ERK 17 . Based on these experimental evidences, which associate PCLI1 to cell signaling, we further investigated the role of PCLI1 in controlling cell growth.…”