Li Q, Chen H.Epigenetic modifications of metastasis suppressor genes in colon cancer metastasis. Epigenetics 6:849-852

Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Epigenetics: official journal of the DNA Methylation Society (Impact Factor: 4.78). 07/2011; 6(7):849-52. DOI: 10.4161/epi.6.7.16314
Source: PubMed


Colon and rectal cancer (colorectal cancer, CRC) is the third most common cancer worldwide. Deaths from CRC account for around 8% of all cancer deaths, making it the fourth most common cause of death from cancer. The high mortality rate of colon cancer is mainly attributable to its metastasis. Efforts have been made to identify metastasis suppressor genes, which encode proteins responsible for inhibiting the metastasis but not suppressing the growth of primary tumors. Studies on metastasis suppressor genes demonstrated that epigenetic modifications, such as DNA promoter methylation and histone modification, play crucial roles in regulating the expression of many metastasis suppressor genes, which indicates the association between aberrant epigenetic alterations and cancer metastasis. This review will focus on the recent findings regarding metastasis suppressors regulated by epigenetic modifications, particularly DNA methylation and histone modification, in CRC metastasis. Also discussed will be recent progress on the suppression of CRC metastasis by genistein, a soy isoflavone, with a focus on epigenetic mechanisms.

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Available from: Qian Li, Apr 03, 2015
    • "Although a significant number of genes associated with cancer metastasis has been reported, causality of epigenetic mechanism in metastasis development, particularly silencing potential metastasis suppressor gene by hypermethylation of CpG islands, has not been well established (Lujambio and Esteller, 2009; Li and Chen, 2011). Recent study conducted by Aryee et al. (2013) suggests that DNA methylation alterations have the potential for producing a selectable driver event in cancer progression. "
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    ABSTRACT: Aberrant HGF-MET signaling activation via interactions with surrounding stromal cells in tumor microenvironment plays significant roles in malignant tumor progression. However, extracellular proteolytic regulation of HGF activation which is influenced by the tumor microenvironment and its consequential effects on melanoma malignancy remain uncharacterized. In this study we identified SPINT2: a proteolytic inhibitor of hepatocyte growth factor activator (HGFA), which plays a significant role in the suppression of the HGF-MET pathway and malignant melanoma progression. SPINT2 expression is significantly lower in metastatic melanoma tissues compared to those in early stage primary melanomas which also corresponded with DNA methylation levels isolated from tissue samples. Treatment with the DNA hypomethylating agent decitabine in cultured melanoma cells induced transcriptional reactivation of SPINT2, suggesting that this gene is epigenetically silenced in malignant melanomas. Furthermore, we show that ectopically expressed SPINT2 in melanoma cells inhibits HGF induced MET-AKT signaling pathway and decreases malignant phenotype potential such as cell motility, and invasive growth of melanoma cells. These results suggest that SPINT2 is associated with tumor suppressive functions in melanoma by inhibiting an extracellular signal regulator of HGF which is typically activated by tumor-stromal interactions. These findings indicate that epigenetic impairment of the tightly regulated cytokine-receptor communications in tumor microenvironment may contribute to malignant tumor progression.Journal of Investigative Dermatology accepted article preview online, 24 April 2015. doi:10.1038/jid.2015.160.
    No preview · Article · Apr 2015 · Journal of Investigative Dermatology
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    • "Colon and rectal cancer (colorectal cancer, CRC), the third most common cancer worldwide, has become one of the leading causes of death from cancers [1]. Surgery, chemotherapy and radiotherapy are the primary and common treatments for colorectal cancer. "
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    ABSTRACT: Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid distributed in medical herbs, exerts antitumor effects and is emerging as a promising compound for cancer prevention and therapy, but its excise mechanisms of action in colon cancer cells remains largely unknown. Here, we identified the molecular mechanisms by which UA inhibited cell proliferation and induced apoptosis in human colon cancer SW480 and LoVo cells. Treatment with UA led to significant inhibitions in cell viability and clone formation and changes in cell morphology and spreading. UA also suppressed colon cancer cell migration by inhibiting MMP9 and upregulating CDH1 expression. Further studies showed that UA inhibited the phosphorylation of Akt and ERK proteins. Pretreatment with an Akt or ERK-specific inhibitor considerably abrogated the proliferation inhibition by UA. UA also significantly inhibited colon cancer cell COX-2 expression and PGE2 production. Pretreatment with a COX-2 inhibitor (celecoxib) abrogated the UA-induced cell proliferation. Moreover, we found that UA effectively promoted NF-κB and p300 translocation from cell nuclei to cytoplasm, and attenuated the p300-mediated acetylation of NF-κB and CREB2. Pretreatment with a p300 inhibitor (roscovitine) abrogated the UA-induced cell proliferation, which is reversed by p300 overexpression. Furthermore, UA treatment induced colon cancer cell apoptosis, increased the cleavage of PARP, caspase-3 and 9, and trigged the release of cytochrome c from mitochondrial inter-membrane space into cytosol. These results indicate that UA inhibits cell proliferation and induces apoptosis in colon cancer cells through simultaneous modulation of the multiple signaling pathways such as MMP9/CDH1, Akt/ERK, COX-2/PGE2, p300/NF-κB/CREB2, and cytochrome c/caspase pathways.
    Preview · Article · May 2013 · PLoS ONE
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    ABSTRACT: Migheli F, Migliore L. Epigenetics of colorectal cancer. Colorectal cancer (CRC) develops through a multistep process that results from the progressive accumulation of mutations and epigenetic alterations in tumor suppressor genes and oncogenes. Epigenetic modifications, that have a fundamental role in the regulation of gene expression, involve DNA methylation, specific histone modifications and non-coding RNAs (ncRNAs) interventions. Many genes have been until now studied to detect their methylation status during CRC carcinogenesis; and the functions of many of these genes in cancer initiation and progression are being clarified. Less is known about the patterns of histone modification alterations in CRC. Epigenetic deregulation of the ncRNAs or the genes involved in their biogenesis have been described in tumor progression and some examples of dysregulated microRNA were found also in CRC cells. Diet has an important role in the etiology of colon cancer. Folate is involved via 5-methyltetrahydrofolate in the conversion of homocysteine to methionine, which is then used to form the main DNA methylating agent S-adenosylmethionine. However, the role of folate in protecting from or in promoting CRC, depending on conditions, is still debated. The study of epigenetic marks to better characterize CRC and to identify new tools for diagnosis and prognosis as well as for therapeutic interventions is extremely promising.
    No preview · Article · Jan 2012 · Clinical Genetics
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