An RNAi screen identifies TRRAP as a regulator of brain tumor-initiating cell differentiation.
Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer associated with a very poor prognosis. Recently, the initiation and growth of GBM has been linked to brain tumor-initiating cells (BTICs), which are poorly differentiated and share features with neural stem cells (NSCs). Here we describe a kinome-wide RNA interference screen to identify factors that control the tumorigenicity of BTICs. We identified several genes whose silencing induces differentiation of BTICs derived from multiple GBM patients. In particular, knockdown of the adaptor protein TRRAP significantly increased differentiation of cultured BTICs, sensitized the cells to apoptotic stimuli, and negatively affected cell cycle progression. TRRAP knockdown also significantly suppressed tumor formation upon intracranial BTIC implantation into mice. Together, these findings support a critical role for TRRAP in maintaining a tumorigenic, stem cell-like state.
Wurdak
Heiko
H
The Skaggs Institute of Chemical Biology and Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Zhu
Shoutian
S
Romero
Angelica
A
Lorger
Mihaela
M
Watson
James
J
Chiang
Chih-Yuan
CY
Zhang
Jay
J
Natu
Vanita S
VS
Lairson
Luke L
LL
Walker
John R
JR
Trussell
Christopher M
CM
Harsh
Griffith R
GR
Vogel
Hannes
H
Felding-Habermann
Brunhilde
B
Orth
Anthony P
AP
Miraglia
Loren J
LJ
Rines
Daniel R
DR
Skirboll
Stephen L
SL
Schultz
Peter G
PG
D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis* / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000737:chemistry* / Q000166:cytology; D009687:Nuclear Proteins / Q000032:analysis* / Q000235:genetics; D034622:RNA Interference; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D009687:Nuclear Proteins; C113829:transformation-transcription domain-associated protein