PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype

Shunlei Duan, Guohong Yuan, Xiaomeng Liu, Ruotong Ren, Jingyi Li, Weizhou Zhang, Jun Wu, Xiuling Xu, Lina Fu, Ying Li, Jiping Yang, Weiqi Zhang, Ruijun Bai, Fei Yi, Keiichiro Suzuki, Hua Gao, Concepcion Rodriguez Esteban, Chuanbao Zhang, Juan Carlos Izpisua Belmonte, Zhiguo ChenXiaomin Wang, Tao Jiang, Jing Qu, Fuchou Tang, Guang Hui Liu

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

PTEN is a tumour suppressor frequently mutated in many types of cancers. Here we show that targeted disruption of PTEN leads to neoplastic transformation of human neural stem cells (NSCs), but not mesenchymal stem cells. PTEN-deficient NSCs display neoplasm-associated metabolic and gene expression profiles and generate intracranial tumours in immunodeficient mice. PTEN is localized to the nucleus in NSCs, binds to the PAX7 promoter through association with cAMP responsive element binding protein 1 (CREB)/CREB binding protein (CBP) and inhibits PAX7 transcription. PTEN deficiency leads to the upregulation of PAX7, which in turn promotes oncogenic transformation of NSCs and instates 'aggressiveness' in human glioblastoma stem cells. In a large clinical database, we find increased PAX7 levels in PTEN-deficient glioblastoma. Furthermore, we identify that mitomycin C selectively triggers apoptosis in NSCs with PTEN deficiency. Together, we uncover a potential mechanism of how PTEN safeguards NSCs, and establish a cellular platform to identify factors involved in NSC transformation, potentially permitting personalized treatment of glioblastoma.

Original languageEnglish (US)
Article number10068
JournalNature communications
Volume6
DOIs
StatePublished - Dec 3 2015

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Duan, S., Yuan, G., Liu, X., Ren, R., Li, J., Zhang, W., Wu, J., Xu, X., Fu, L., Li, Y., Yang, J., Zhang, W., Bai, R., Yi, F., Suzuki, K., Gao, H., Esteban, C. R., Zhang, C., Belmonte, J. C. I., ... Liu, G. H. (2015). PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype. Nature communications, 6, [10068]. https://doi.org/10.1038/ncomms10068