Back to Search
Start Over
From the Cover: Neutralization of terminal differentiation in gliomagenesis.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2013 Sep 03; Vol. 110 (36), pp. 14520-7. Date of Electronic Publication: 2013 Aug 05. - Publication Year :
- 2013
-
Abstract
- An immature state of cellular differentiation--characterized by stem cell-like tendencies and impaired differentiation--is a hallmark of cancer. Using glioblastoma multiforme (GBM) as a model system, we sought to determine whether molecular determinants that drive cells toward terminal differentiation are also genetically targeted in carcinogenesis and whether neutralizing such genes also plays an active role to reinforce the impaired differentiation state and promote malignancy. To that end, we screened 71 genes with known roles in promoting nervous system development that also sustain copy number loss in GBM through antineoplastic assay and identified A2BP1 (ataxin 2 binding protein 1, Rbfox1), an RNA-binding and splicing regulator that is deleted in 10% of GBM cases. Integrated in silico analysis of GBM profiles to elucidate the A2BP1 pathway and its role in glioma identified myelin transcription factor 1-like (Myt1L) as a direct transcriptional regulator of A2BP1. Reintroduction of A2BP1 or Myt1L in GBM cell lines and glioma stem cells profoundly inhibited tumorigenesis in multiple assays, and conversely, shRNA-mediated knockdown of A2BP1 or Myt1L in premalignant neural stem cells compromised neuronal lineage differentiation and promoted orthotopic tumor formation. On the mechanistic level, with the top-represented downstream target TPM1 as an illustrative example, we demonstrated that, among its multiple functions, A2BP1 serves to regulate TPM1's alternative splicing to promote cytoskeletal organization and terminal differentiation and suppress malignancy. Thus, in addition to the activation of self-renewal pathways, the neutralization of genetic programs that drive cells toward terminal differentiation may also promote immature and highly plastic developmental states that contribute to the aggressive malignant properties of GBM.
- Subjects :
- Animals
Brain Neoplasms metabolism
Brain Neoplasms pathology
Carcinogenesis metabolism
Carcinogenesis pathology
Cells, Cultured
Female
Gene Expression Profiling
Glial Fibrillary Acidic Protein genetics
Glial Fibrillary Acidic Protein metabolism
Glioblastoma metabolism
Glioblastoma pathology
Humans
Immunohistochemistry
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Nude
Mice, SCID
Mice, Transgenic
Neoplastic Stem Cells metabolism
Neoplastic Stem Cells pathology
Nerve Tissue Proteins genetics
Nerve Tissue Proteins metabolism
Neural Stem Cells metabolism
Neural Stem Cells pathology
Oligonucleotide Array Sequence Analysis
RNA Interference
RNA Splicing Factors
RNA-Binding Proteins genetics
RNA-Binding Proteins metabolism
Transcription Factors genetics
Transcription Factors metabolism
Transplantation, Heterologous
Brain Neoplasms genetics
Carcinogenesis genetics
Cell Differentiation genetics
Glioblastoma genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 110
- Issue :
- 36
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 23918370
- Full Text :
- https://doi.org/10.1073/pnas.1308610110