TY - JOUR
T1 - PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype
AU - Duan, Shunlei
AU - Yuan, Guohong
AU - Liu, Xiaomeng
AU - Ren, Ruotong
AU - Li, Jingyi
AU - Zhang, Weizhou
AU - Wu, Jun
AU - Xu, Xiuling
AU - Fu, Lina
AU - Li, Ying
AU - Yang, Jiping
AU - Zhang, Weiqi
AU - Bai, Ruijun
AU - Yi, Fei
AU - Suzuki, Keiichiro
AU - Gao, Hua
AU - Esteban, Concepcion Rodriguez
AU - Zhang, Chuanbao
AU - Belmonte, Juan Carlos Izpisua
AU - Chen, Zhiguo
AU - Wang, Xiaomin
AU - Jiang, Tao
AU - Qu, Jing
AU - Tang, Fuchou
AU - Liu, Guang Hui
N1 - 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.
PY - 2015/12/3
Y1 - 2015/12/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84949184647&partnerID=8YFLogxK
U2 - 10.1038/ncomms10068
DO - 10.1038/ncomms10068
M3 - Article
C2 - 26632666
AN - SCOPUS:84949184647
SN - 2041-1723
VL - 6
JO - Nature Communications
JF - Nature Communications
M1 - 10068
ER -