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The Wnt/?-catenin/T-cell factor 4 pathway up-regulates high-mobility group A1 expression in colon cancer.

ABSTRACT: High-mobility group A1 (HMGA1) encodes proteins that act as mediators in viral integration, modification of chromatin structure, neoplastic transformation and metastatic progression. Because HMGA1 is overexpressed in most cancers and has transcriptional relationships with several Wnt-responsive genes, we explored the involvement of HMGA1 in Wnt/?-catenin/TCF-4 signalling. In adenomatous polyposis coli (APC(Min/+)) mice, we observed significant up-regulation of HMGA1 mRNA and protein in intestinal tumours when compared with normal intestinal mucosa. Conversely, restoration of Wnt signalling by the zinc induction of wild-type APC resulted in HMGA1 down-regulation in HT-29 cells. Because APC mutations are associated with mobilization of the ?-catenin/TCF-4 transcriptional complex and subsequent activation of downstream oncogenic targets, we analyzed the 5'-flanking sequence of HMGA1 for putative TCF-4 binding elements. We identified two regions that specifically bind the ?-catenin/TCF-4 complex in vitro and in vivo, identifying HMGA1 as an immediate target of the ?-catenin/TCF-4 signalling pathway in colon cancer. Collectively, these findings strongly implicate Wnt/?-catenin/TCF-4 signalling in regulating HMGA1 to further expand the extensive regulatory network affected by Wnt/?-catenin/TCF-4 signalling.

SUBMITTER: Bush BM

PROVIDER: S-EPMC3616152 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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The Wnt/β-catenin/T-cell factor 4 pathway up-regulates high-mobility group A1 expression in colon cancer.

Bush Bethany M BM Brock Ashton T AT Deng Jiayue A JA Nelson Ronald A RA Sumter Takita Felder TF

Cell biochemistry and function 20120907 3

High-mobility group A1 (HMGA1) encodes proteins that act as mediators in viral integration, modification of chromatin structure, neoplastic transformation and metastatic progression. Because HMGA1 is overexpressed in most cancers and has transcriptional relationships with several Wnt-responsive genes, we explored the involvement of HMGA1 in Wnt/β-catenin/TCF-4 signalling. In adenomatous polyposis coli (APC(Min/+)) mice, we observed significant up-regulation of HMGA1 mRNA and protein in intestina ...[more]

PMID: 22961697

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Project description:Lysine-specific demethylase 1 (LSD1) is widely involved in the proliferation, invasion, and metastasis of cancers. However, it is uncertain whether LSD1 plays a role in facilitating colon cancer progression. Here, we have clarified the molecular mechanism by which LSD1 interacts with X-ray repair cross complementing protein 5 (Ku80) to promote colon cancer progression by directly targeting forehead protein transcription factor 2 (FOXF2). First, the interacting proteins of LSD1 were identified by immunoprecipitation and mass spectrometry. The expression of Ku80 and FOXF2 in colon cancer was detected using immunohistochemistry, real-time quantitative transcription polymerase chain reaction, and western blot. Next, the proliferation, invasion, and metastasis of colon cancer in vitro and in vivo were detected by methyl thiazolyl tetrazolium, 5-ethynyl-20-deoxyuridine, colony formation, wound healing, and nude mice xenograft model assays, respectively. Chromatin immunoprecipitation (ChIP) and ChIP-PCR were performed to investigate the molecular mechanism of LSD1 and Ku80 in colon cancer. Our results indicated that Ku80 expression was positively correlated with the invasion and migration of colon cancer cells, and negatively correlated with FOXF2 expression. More importantly, the high expression of Ku80 and the low expression of FOXF2 were particularly associated with driving the progression of colon cancer. Ku80 knockdown and LSD1 silencing inhibited the proliferation, migration, and invasion of colon cancer in vitro and in vivo. Mechanically, LSD1 interacts with Ku80 and also binds directly to the 687-887-bp portion of the FOXF2 promoter region. The upregulated methylation level of H3K4me2 in the FOXF2 promoter region facilitated the transcriptional activation of FOXF2, and downregulated protein expression associated with the Wnt/β-catenin signaling pathway. In conclusion, our study suggests that LSD1 regulates the FOXF2-mediated Wnt/β-catenin signaling pathway by interacting with Ku80, promoting the malignant biological properties of colon cancer, highlighting the binding of LSD1 and Ku80 as a useful anti-cancer target for colon cancer.

Project description:Objective: Studies suggest that matrix Gla protein (MGP) is associated with osteoporosis. However, the precise mechanism through which MGP regulates bone metabolism is not fully understood. The purpose of this study was to clarify the role of MGP in bone metabolism. Methods: The MGP gene in MG63 cell line was knocked down using shRNA. Cell Counting Kit-8 assay was used to detect the proliferation of MG63 cells. Moreover, the differentiation and mineralization of MG63 cells were measured through alkaline phosphatase staining and Alizarin Red S staining. Western blotting and quantitative reverse transcription-polymerase chain reaction were conducted to detect the protein and mRNA levels of components of the Wnt/β-catenin signaling pathway, such as Wnt3a, β-catenin, and Runx2. Transgenic (MGP+) mice were used to detect the effects of MGP in vivo. Results: The Cell Counting Kit-8 assay suggested that upregulated MGP could promote the proliferation of MG63 cells, whereas its downregulation inhibited proliferation. The alkaline phosphatase assay and Alizarin Red S staining showed that overexpressed MGP led to prominently upregulated differentiation and mineralization of MG63 cells. Conversely, knockdown of MGP decreased the levels of differentiation and mineralization. Western blotting and quantitative reverse transcription-polymerase chain reaction showed that overexpression of MGP upregulated Wnt3a, β-catenin, and Runx2. In contrast, knocking down MGP reduced their transcriptional levels. In vivo, overexpression of MGP inhibited the decrease in bone mineral density induced via ovariectomy in the femur, and significantly prevented bone volume fraction, trabecular number, BV/TV, and TbTh to decrease. In addition, it increased the levels of estradiol in sera. Conclusion: The findings of this study suggest that the promotion of osteoblast proliferation, differentiation, and mineralization by MGP may be a mechanism to prevent osteoporosis. Furthermore, the results show that MGP promoted the osteogenic effects via the Wnt/β-catenin signaling pathway.

Dataset Information

The Wnt/?-catenin/T-cell factor 4 pathway up-regulates high-mobility group A1 expression in colon cancer.

Publications

The Wnt/β-catenin/T-cell factor 4 pathway up-regulates high-mobility group A1 expression in colon cancer.

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