Neutralization of terminal differentiation in gliomagenesis

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 RNAbinding 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.oncogenomics | cancer stem cells

Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact

“…26 Other studies have suggested that halted differentiation of neuroprogenitor cells is an early step in gliomagenesis. 27 Since HCMV proteins and nucleotide sequences seem to be present in most GBMs 16,[28][29][30] and that HCMV-IE expression is a prognostic marker for poor patient survival irrespective of the GBM subtype, 18 our present model of HCMV infection of primary GBM cells appears to recapitulate early events during glioma development.…”

Ataxin-2 binding protein 1 is a context-specific positive regulator of Notch signaling during neurogenesis inDrosophila melanogaster

“…For instance, in C. elegans the A2BP1 ortholog acts as a dose-sensitive sex determinant (Hodgkin et al, 1994). In vertebrates, loss of A2BP1 leads to tumorigenesis, including glioma and neuroblastoma (Hu et al, 2013). In Drosophila, loss of A2BP1 during oogenesis leads to the tumorigenic phenotype of the egg chamber (Tastan et al, 2010).…”

Quantitative proteomic analyses of mammary organoids reveals distinct signatures after exposure to environmental chemicals

“…The observation of differentially expressed proteins translated from alternative splice variants, many of which function in cell growth and differentiation in cancer (8,73), is intriguing. Alternative splicing significantly increases functional gene diversity, and aberrant splicing contributes to tumor progression and resistance to cancer therapy (59).…”