Division of Hematology/Oncology, Department of Medicine, Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL 60611, USA.
Oncogene. 2010 Sep 30;29(39):5370-80. doi: 10.1038/onc.2010.269. Epub 2010 Jul 12.
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.
神经元排斥物 SLIT2 在许多癌症类型中主要通过启动子超甲基化被抑制。然而，SLIT2 在前列腺癌中尚未被研究过。通过全基因组定位分析，我们确定 SLIT2 是多梳蛋白（PcG）蛋白 EZH2 的靶标。含有 EZH2 的多梳抑制复合物结合到 SLIT2 启动子上，抑制其表达。SLIT2 在大多数转移性前列腺肿瘤中下调，与 EZH2 呈负相关。这种受抑制的表达可以通过甲基化抑制剂或 EZH2 抑制化合物来恢复。此外，SLIT2 表达水平低与侵袭性前列腺癌、乳腺癌和肺癌相关。功能分析表明，SLIT2 抑制前列腺癌细胞的增殖和侵袭。因此，这项研究首次显示了 SLIT2 在前列腺肿瘤中的表观遗传沉默，并支持 SLIT2 作为侵袭性实体瘤的潜在生物标志物。重要的是，PcG 介导的抑制可能是癌症中 SLIT2 被 DNA 甲基化沉默的前兆。
