The neuronal repellent SLIT2 is a target for repression by EZH2 in prostate cancer.
The neuronal repellent SLIT2 is repressed in a number of cancer types primarily through promoter hypermethylation. SLIT2, however, has not been studied in prostate cancer. Through genome-wide location analysis we identified SLIT2 as a target of polycomb group (PcG) protein EZH2. The EZH2-containing polycomb repressive complexes bound to the SLIT2 promoter inhibiting its expression. SLIT2 was downregulated in a majority of metastatic prostate tumors, showing a negative correlation with EZH2. This repressed expression could be restored by methylation inhibitors or EZH2-suppressing compounds. In addition, a low level of SLIT2 expression was associated with aggressive prostate, breast and lung cancers. Functional assays showed that SLIT2 inhibited prostate cancer cell proliferation and invasion. Thus, this study showed for the first time the epigenetic silencing of SLIT2 in prostate tumors, and supported SLIT2 as a potential biomarker for aggressive solid tumors. Importantly, PcG-mediated repression may serve as a precursor for the silencing of SLIT2 by DNA methylation in cancer.
Yu
J
J
Division of Hematology/Oncology, Department of Medicine, Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL 60611, USA. jindan-yu@northwestern.edu
Cao
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Q
Yu
J
J
Wu
L
L
Dallol
A
A
Li
J
J
Chen
G
G
Grasso
C
C
Cao
X
X
Lonigro
R J
RJ
Varambally
S
S
Mehra
R
R
Palanisamy
N
N
Wu
J Y
JY
Latif
F
F
Chinnaiyan
A M
AM
D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D000098552:Slit Homolog 2 Protein
D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D000098552:Slit Homolog 2 Protein