Abstract
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.
Original language | English (US) |
---|---|
Pages (from-to) | 5370-5380 |
Number of pages | 11 |
Journal | Oncogene |
Volume | 29 |
Issue number | 39 |
DOIs | |
State | Published - Sep 30 2010 |
Funding
This study was supported in part by the NIH Prostate Specialized Program of Research Excellence Grants P50CA69568 and P50CA090386, Early Detection Research Network Grant UO1 111275 (to AMC), the NIH 1R01CA132874-01A1 (to AMC), CA114197 and CA107193 (to JYW) and K99CA129565-01A1 (to JY), the US Department of Defense PC051081 (to AMC) and PC080665 (to JY), and the James S McDonnell Foundation Grant JSMF (to JYW) and Searle Foundation (to JYW). AMC is supported by a Burroughs Welcome Foundation Award in Clinical Translational Research, a Doris Duke Charitable Foundation Distinguished Clinical Investigator Award, the Prostate Cancer Foundation and the Howard Hughes Medical Institute. AMC is an American Cancer Society Research Professor.
Keywords
- DNA hypermethylation
- EZH2
- Epigenetic silencing
- Polycomb group proteins
- Prostate cancer
- SLIT2
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research