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

Qi Cui (1) , Su Yang (1) , Peng Ye (1) , E. Tian (1) , Guoqiang Sun (1) , Jiehua Zhou (1) , Guihua Sun (1) , Xiaoxuan Liu (2) , Chao Chen (2) , Kiyohito Murai (1) , Chunnian Zhao (1) , Krist T. Azizian (1) , Lu Yang (1) , Charles Warden (1) , Xiwei Wu (1) , Massimo d'Apuzzo (1) , Christine Brown (1) , Behnam Badie (1) , Ling Peng (2) , Arthur D. Riggs (1) , John J. Rossi (1) , Yanhong Shi (1)

1 Beckman Research Institute of City of Hope
2 CINaM - Centre Interdisciplinaire de Nanoscience de Marseille

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.

Mots clés: Cancer stem cells; Cell signalling; CNS cancer; Self-renewal

Domaines: Biophysique

Qi Cui, Su Yang, Peng Ye, E. Tian, Guoqiang Sun, et al.. Downregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesis. Nature Communications, 2016, 7, pp.10637. ⟨10.1038/ncomms10637⟩. ⟨hal-01452670⟩