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 down-regulated in a majority of metastatic prostate tumors exhibiting 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 demonstrated for the first time 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.
RATIONALE:Successful host defense against the fungal pathogen Cryptococcus neoformans (Cneo) requires an adaptive T1 immune response associated with the CCR2−mediated recruitment to the lungs of large numbers of CD11c+ dendritic cells (DC). The specific precursors of these lung DC are unknown. We investigated whether a circulating monocyte and/or pre−DC population was the source of the recruited lung DC in this model system. METHODS: We infected unprimed wild−type CCR2+/+ or CCR2−/− (BALB/c) mice with Cneo by the intratracheal route. We used 8−color flow cytometric analysis to identify DC, monocytes, macrhophages, and their potential precursors within lung, lung associated lymph node (LALN), peripheral blood mononuclear cells (PBMC), and bone marrow from uninfected mice and at 7, 10, 14, 21, and 28 days post−infection.
RESULTS:The accumulation of lung DC and monocytes (in CCR2+/+ mice) was associated with a marked rise in a specific Ly6C−high, CD11b+ monocyte population in the bone marrow, PBMC, and lung. This population was significantly diminished in the blood and lungs of CCR2−/− mice. In contrast, an alternative potential precursor of lung DC, peripheral blood CD11c+, MHC Class II+ cells, were: a) less frequent at baseline, b) increased minimally in response to infection, and c) did not differ between CCR2+/+ and CCR2−/− mice. In both strains of mice, relatively few DC were identified in the LALN. CONCLUSION: In response to Cneo infection in the lung, CCR2 mediates the release of Ly6C−high, CD11b+ monocytes from the bone marrow into the peripheral blood. Our data support the hypothesis that this monocyte population develops into inflammatory lung DC, which function locally to promote protective T1 immune responses against fungal pneumonia. This abstract is funded by: Biomedical Research &Development Service, Department of Veterans Affairs.
Am J Respir Crit Care Med
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