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PID1 (NYGGF4), a new growth-inhibitory gene in embryonal brain tumors and gliomas
Anat Erdreich-Epstein1, Nathan Robison, Xiuhai Ren
1Authors' Affiliations: Departments of Pediatrics, Pathology, Radiology, and Neurosurgery, at the Saban Research Institute at Children's Hospital Los Angeles, Norris Comprehensive Cancer Center; Departments of Preventive Medicine and Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California; Division of Pediatric Neurooncology at the German Cancer Research Center DKFZ; and Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
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 (GBM), the most malignant gliomas, compared with other astrocytomas, oligodendrogliomas and nontumor brains. Neural and proneural GBM subtypes had higher PID1 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 PID1 mRNA also correlated with longer overall survival in patients with glioma and GBM. 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 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.
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.
Insights
Phosphotyrosine Interaction Domain containing 1 (PID1) is lower in aggressive brain tumors like medulloblastoma and glioblastoma. Higher PID1 levels correlate with better patient survival, suggesting a tumor-inhibitory role for PID1 in cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- PID1 (Phosphotyrosine Interaction Domain containing 1; NYGGF4) was initially identified for its role in insulin signaling and mitochondrial function.
- Its involvement in cancer has not been previously reported.
Purpose of the Study:
- To investigate the role of PID1 in cancer, specifically in medulloblastoma and glioma.
- To determine if PID1 expression levels correlate with tumor characteristics and patient outcomes.
Main Methods:
- Analysis of PID1 mRNA levels in independent medulloblastoma and glioma datasets.
- Correlation of PID1 expression with tumor subtypes, histology, and patient survival (overall and progression-free).
- In vitro studies involving PID1 overexpression and knockdown in cancer cell lines (medulloblastoma, ATRT, GBM) to assess effects on cell proliferation, apoptosis, and mitochondrial function.
Main Results:
- Lower mean PID1 mRNA levels were observed in unfavorable medulloblastomas (groups 3 and 4) and glioblastomas (GBM) compared to favorable subtypes and non-tumor brain tissue.
- Higher PID1 mRNA levels correlated with longer overall survival and radiation-free progression-free survival in medulloblastoma and glioma patients.
- Overexpression of PID1 inhibited colony formation, increased cell death and apoptosis, and impaired mitochondrial function in medulloblastoma, ATRT, and GBM cell lines.
Conclusions:
- PID1 expression is significantly altered in medulloblastoma and glioma, with lower levels associated with more aggressive tumors.
- PID1 may function as a tumor suppressor in these brain cancers.
- PID1 warrants further investigation as a potential therapeutic target or biomarker in oncology.
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