Downregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesis

Qi Cui, Su Yang, Peng Ye, E. Tian, Guoqiang Sun, Jiehua Zhou, Guihua Sun, Xiaoxuan Liu, Chao Chen, Kiyohito Murai, Chunnian Zhao, Krist T. Azizian, Lu Yang, Charles Warden, Xiwei Wu, Massimo D'Apuzzo, Christine Brown, Behnam Badie, Ling Peng, Arthur D. Riggs, John J. Rossi and Yanhong Shi ()
Additional contact information
Qi Cui: Cancer Center, Beckman Research Institute of City of Hope
Su Yang: Cancer Center, Beckman Research Institute of City of Hope
Peng Ye: Cancer Center, Beckman Research Institute of City of Hope
E. Tian: Cancer Center, Beckman Research Institute of City of Hope
Guoqiang Sun: Cancer Center, Beckman Research Institute of City of Hope
Jiehua Zhou: Beckman Research Institute of City of Hope
Guihua Sun: Beckman Research Institute of City of Hope
Xiaoxuan Liu: Aix-Marseille Université, CNRS, UMR 7325, Centre Interdisciplinaire de Nanoscience de Marseille
Chao Chen: Aix-Marseille Université, CNRS, UMR 7325, Centre Interdisciplinaire de Nanoscience de Marseille
Kiyohito Murai: Cancer Center, Beckman Research Institute of City of Hope
Chunnian Zhao: Cancer Center, Beckman Research Institute of City of Hope
Krist T. Azizian: Beckman Research Institute of City of Hope
Lu Yang: Integrative Genomics Core, Beckman Research Institute of City of Hope
Charles Warden: Integrative Genomics Core, Beckman Research Institute of City of Hope
Xiwei Wu: Integrative Genomics Core, Beckman Research Institute of City of Hope
Massimo D'Apuzzo: Beckman Research Institute of City of Hope
Christine Brown: Beckman Research Institute of City of Hope
Behnam Badie: Beckman Research Institute of City of Hope
Ling Peng: Aix-Marseille Université, CNRS, UMR 7325, Centre Interdisciplinaire de Nanoscience de Marseille
Arthur D. Riggs: Beckman Research Institute of City of Hope
John J. Rossi: Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope
Yanhong Shi: Cancer Center, Beckman Research Institute of City of Hope

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: Abstract Glioblastomas have been proposed to be maintained by highly tumorigenic glioblastoma stem cells (GSCs) that are resistant to current therapy. Therefore, targeting GSCs is critical for developing effective therapies for glioblastoma. In this study, we identify the regulatory cascade of the nuclear receptor TLX and the DNA hydroxylase Ten eleven translocation 3 (TET3) as a target for human GSCs. We show that knockdown of TLX expression inhibits human GSC tumorigenicity in mice. Treatment of human GSC-grafted mice with viral vector-delivered TLX shRNA or nanovector-delivered TLX siRNA inhibits tumour development and prolongs survival. Moreover, we identify TET3 as a potent tumour suppressor downstream of TLX to regulate the growth and self-renewal in GSCs. This study identifies the TLX-TET3 axis as a potential therapeutic target for glioblastoma.

Date: 2016
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DOI: 10.1038/ncomms10637

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