Dataset Information

Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer.

ABSTRACT: SRY-box containing gene 17 (Sox17) is a member of the high mobility group (HMG) transcription factor superfamily, which plays critical roles in the regulation of development and stem/precursor cell function, at least partly through repression of Wnt pathway activity. Modulators controlling aberrant Wnt signaling activation are frequently disrupted in human cancers through complementary effects of epigenetic and genetic changes. Our recent global analysis of CpG island hypermethylation and gene expression in colorectal cancer (CRC) cell lines revealed that SOX17 gene silencing is associated with DNA hypermethylation of a CpG island in the promoter region. Here, we report that CpG island methylation-dependent silencing of SOX17 occurs in 100% of CRC cell lines, 86% of colorectal adenomas, 100% of stage I and II CRC, 89% of stage III CRC, 89% of primary esophageal cancer, and 50% of non-small cell lung cancer. Overexpression of SOX17 in HCT116 CRC cells inhibits colony growth and beta-catenin/T-cell factor-dependent transcription. Structure-based deletion analysis further shows the presence of a Wnt signaling repression domain in the SOX17 HMG box. Together, our studies suggest that SOX17 is a negative modulator of canonical Wnt signaling, and that SOX17 silencing due to promoter hypermethylation is an early event during tumorigenesis and may contribute to aberrant activation of Wnt signaling in CRC.

SUBMITTER: Zhang W

PROVIDER: S-EPMC2823123 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer.

Zhang Wei W Glöckner Sabine C SC Guo Mingzhou M Machida Emi Ota EO Wang David H DH Easwaran Hariharan H Van Neste Leander L Herman James G JG Schuebel Kornel E KE Watkins D Neil DN Ahuja Nita N Baylin Stephen B SB

Cancer research 20080401 8

SRY-box containing gene 17 (Sox17) is a member of the high mobility group (HMG) transcription factor superfamily, which plays critical roles in the regulation of development and stem/precursor cell function, at least partly through repression of Wnt pathway activity. Modulators controlling aberrant Wnt signaling activation are frequently disrupted in human cancers through complementary effects of epigenetic and genetic changes. Our recent global analysis of CpG island hypermethylation and gene e ...[more]

PMID: 18413743

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Project description:Objective:Hepcidin deficiency is known to cause body iron accumulation and bone microarchitecture defects, but the exact underlying mechanisms of hepcidin deficiency-induced bone loss remain unclear. Our objective was to understand the molecular mechanism of hepcidin deficiency-induced bone loss. Methods:The bone phenotypes of wild type (WT) and hepcidin knockout (Hepcidin-KO) mice were measured by microcomputed tomography. The osteoclastic marker of the bone was measured by tartrate-resistant acid phosphatase staining. The osteoblastic marker of the bone was measured by immunostaining of osteocalcin. Primary osteoblastic and osteoclastic differentiation was performed using bone marrow cells. The mature osteoclast was determined by tartrate-resistant acid phosphatase staining, pit formation assay and relative gene expression. The mature osteoblast was determined by alkaline phosphatase activity, alkaline phosphatase staining, Alizarin Red staining and relative gene expression. The protein expression of ?-catenin, TCF4/TCF7L2 and Forkhead box O3a (FOXO3a) was measured by Western blot and their combination by co-immunoprecipitation. In vivo study was performed by tail vein administration of FOXO3a-RNAi using an adeno-associated virus in Hepcidin-KO mice. Results:We found that Hepcidin-KO mice exhibited iron accumulation and bone loss compared with WT mice. The osteoclastic differentiation of bone marrow-derived macrophages from Hepcidin-KO mice was not significantly different from that of bone marrow-derived macrophages from WT mice. However, the osteoblastic differentiation of bone marrow-derived mesenchymal stem cells from Hepcidin-KO mice was obviously decreased compared with that of bone marrow-derived mesenchymal stem cells from WT mice. Furthermore, it was confirmed in this study that upon hepcidin deficiency, ?-catenin, TCF4/TCF7L2 and FOXO3a expression in bone tissues was not altered, but ?-catenin combination with TCF4/TCF7L2 was strongly inhibited by ?-catenin combination with FOXO3a, indicating that the canonical Wnt/?-catenin pathway was affected. Tail vein administration of FOXO3a-RNAi using an adeno-associated virus in Hepcidin-KO mice resulted in bone mass recovery. Conclusion:These findings suggested that hepcidin deficiency might cause bone loss by interfering with the canonical Wnt/?-catenin pathway via FOXO3a, and FOXO3a inhibition would be a possible approach to treat hepcidin deficiency-induced bone loss. The translational potential of this article:Hepcidin deficiency, as well as iron accumulation, has been considered as a risk factor for osteoporosis. For this kind of osteoporosis, inhibition of FOXO3a either by neutralized antibody or AAV-mediated RNAi, represents an effective and promising method.

Dataset Information

Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer.

Publications

Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer.

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