A genetic screen for candidate tumor suppressors identifies REST.
Tumorigenesis is a multistep process characterized by a myriad of genetic and epigenetic alterations. Identifying the causal perturbations that confer malignant transformation is a central goal in cancer biology. Here we report an RNAi-based genetic screen for genes that suppress transformation of human mammary epithelial cells. We identified genes previously implicated in proliferative control and epithelial cell function including two established tumor suppressors, TGFBR2 and PTEN. In addition, we uncovered a previously unrecognized tumor suppressor role for REST/NRSF, a transcriptional repressor of neuronal gene expression. Array-CGH analysis identified REST as a frequent target of deletion in colorectal cancer. Furthermore, we detect a frameshift mutation of the REST gene in colorectal cancer cells that encodes a dominantly acting truncation capable of transforming epithelial cells. Cells lacking REST exhibit increased PI(3)K signaling and are dependent upon this pathway for their transformed phenotype. These results implicate REST as a human tumor suppressor and provide a novel approach to identifying candidate genes that suppress the development of human cancer.
Westbrook
Thomas F
TF
Howard Hughes Medical Institute, Department of Genetics, Harvard Partners Center for Genetics and Genomics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
Martin
Eric S
ES
Schlabach
Michael R
MR
Leng
Yumei
Y
Liang
Anthony C
AC
Feng
Bin
B
Zhao
Jean J
JJ
Roberts
Thomas M
TM
Mandel
Gail
G
Hannon
Gregory J
GJ
Depinho
Ronald A
RA
Chin
Lynda
L
Elledge
Stephen J
SJ
D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034622:RNA Interference / Q000502:physiology; D012097:Repressor Proteins / Q000494:pharmacology / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000494:pharmacology / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology; D000099229:RE1-Silencing Transcription Factor
D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012097:Repressor Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000099229:RE1-Silencing Transcription Factor