From the Cover: Neutralization of terminal differentiation in gliomagenesis.

TitleFrom the Cover: Neutralization of terminal differentiation in gliomagenesis.
Publication TypeJournal Article
Year of Publication2013
AuthorsHu J, Ho AL, Yuan L, Hu B, Hua S, Hwang SSarah, Zhang J, Hu T, Zheng H, Gan B, Wu G, Wang YAlan, Chin L, DePinho RA
JournalProc Natl Acad Sci U S A
Volume110
Issue36
Pagination14520-7
Date Published2013 Sep 03
ISSN1091-6490
KeywordsAnimals, Brain Neoplasms, Carcinogenesis, Cell Differentiation, Cells, Cultured, Female, Gene Expression Profiling, Glial Fibrillary Acidic Protein, Glioblastoma, Humans, Immunohistochemistry, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Nude, Mice, SCID, Mice, Transgenic, Neoplastic Stem Cells, Nerve Tissue Proteins, Neural Stem Cells, Oligonucleotide Array Sequence Analysis, RNA Interference, RNA Splicing Factors, RNA-Binding Proteins, Transcription Factors, Transplantation, Heterologous
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.

DOI10.1073/pnas.1308610110
Alternate JournalProc Natl Acad Sci U S A
PubMed ID23918370
Grant List5K99CA172700 / CA / NCI NIH HHS / United States
P01 5P01CA095616 / CA / NCI NIH HHS / United States
U01 5U01CA084313 / CA / NCI NIH HHS / United States
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Hongwu Zheng, Ph.D.

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