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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

110 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

Bibliographical note

Funding Information:
We are grateful to Jianfeng Lei from the Capital Medical University and Yihui Xu from Institute of Biophysics for technical assistance, and Yang Zhao for administrative assistance. This work was supported by the National Basic Research Program of China (973 Program, 2015CB964800; 2014CB910503; 2014CB964600; 2012CB966704; 2011CB504100), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA01020312), the Beijing Natural Science Foundation (7141005; 5142016), the National High Technology Research and Development Program of China (2015AA020307), the National Natural Science Foundation of China (NSFC: 81330008; 31222039; 31201111; 81371342; 81300261; 81300677; 81271266; 81471414; 81422017; 81401159; 31322039), the Program of Beijing Municipal Science and Technology Commission (Z151100003915072), the Key Research Program of the Chinese Academy of Sciences (KJZDEW-TZ-L05), the Thousand Young Talents program of China, National Laboratory of Biomacromolecules (012kf02;2013kf05;2013kf11;2014kf02;2015kf10), the State Key Laboratory of Drug Research (SIMM1302KF-17) and the China Postdoctoral Science Foundation Grant (2013M530751). J.C.I.B. was supported by the Salk Institute Cancer Center Support Grant, Universidad Católica San Antonio de Murcia (UCAM), the G. Harold and Leila Y. Mathers Charitable Foundation and the Leona M. and Harry B. Helmsley Charitable Trust (PG-2012-MED002). W.Z. was supported by NIH grants K99/ R00 CA158055, the V Scholar award, American Cancer Society seed grant, Breast Cancer Research Award and Oberley Award (National Cancer Institute Award P30CA086862) from Holden Comprehensive Cancer Center at the University of Iowa, and startup funds from the Department of Pathology, University of Iowa.

ASJC Scopus subject areas

  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology

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