Neutralization of terminal differentiation in gliomagenesis

Jian Hu, Allen L. Ho, Liang Yuan, Baoli Hu, Sujun Hua, Soyoon Sarah Hwang, Jianhua Zhang, Tianyi Hu, Hongwu Zheng, Boyi Gan, Gongxiong Wu, Yaoqi Alan Wang, Lynda Chin, Ronald A. DePinho

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)14520-14527
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number36
DOIs
StatePublished - Sep 3 2013

Keywords

  • Cancer stem cells
  • Oncogenomics

ASJC Scopus subject areas

  • General

MD Anderson CCSG core facilities

  • Research Animal Support Facility
  • Small Animal Imaging Facility

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