Upregulation of DNA Methyltransferase–Mediated Gene Silencing, Anchorage-Independent Growth, and Migration of Colon Cancer Cells by Interleukin-6

Foran, Eílis; Garrity‐Park, Megan; Mureau, Coralie; Newell, John; Smyrk, Thomas C.; Limburg, Paul J.; Egan, Laurence J.

doi:10.1158/1541-7786.mcr-09-0496

Cited by 138 publications

(93 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As already mentioned, IL-6 activates several intracellular signaling pathways, which can stimulate transcription of DNMT1. In colon cancer cells, IL-6 was also shown to mediate gene silencing via epigenetic DNA methylation by DNMT1 involving STAT signaling (32). In malignant T-lymphocytes, DNMT1 was stimulated by STAT3, which binds to the promoter of DNMT1 (33).…”

Section: Discussionmentioning

confidence: 99%

Homocysteine Suppresses the Expression of the Collagen Cross-linker Lysyl Oxidase Involving IL-6, Fli1, and Epigenetic DNA Methylation

Thaler

Agsten

Spitzer

et al. 2011

Journal of Biological Chemistry

107

View full text Add to dashboard Cite

Elevated homocysteine (Hcys) serum levels represent a risk factor for several chronic pathologies, including cardiovascular disease, atherosclerosis, and chronic renal failure, and affect bone development, quality, and homeostasis. Hcys influences the formation of a stable bone matrix directly through the inhibition of the collagen cross-linking enzyme lysyl oxidase (Lox) and, as we have shown recently, by repressing its mRNA expression. The aim of this study was to investigate the mechanisms involved in this process. Epidemiological studies have shown that high homocysteine (Hcys) 2 serum levels represent a risk factor for several chronic disorders such as cardiovascular disease, atherosclerosis, chronic renal failure, diabetes, or the metabolic syndrome (1, 2). Moreover, hyperhomocysteinemia is known to affect bone development and homeostasis (3-6). Hcys has been shown to interfere with post-translational modifications of collagen directly by inhibiting lysyl oxidase (Lox) (7) and indirectly by down-regulation of its mRNA expression and of other genes involved in collagen cross-linking. Enzymatic inhibition or mRNA down-regulation of Lox results in changes in collagen cross-linking pattern in vitro (8 -10) and in vivo resulting in decreased bone quality (11)(12)(13). In this context, we have recently reported a correlation between plasma Hcys levels and a collagen cross-link ratio in forming trabecular surfaces in human bone (14).Lysyl oxidase was also identified as a phenotypic suppressor of the ras oncogene in H-ras-transformed NIH3T3 fibroblasts. In this transformed cell line, H-ras participates in an elaborate pathway attenuating the expression of Lox and of many other genes by CpG methylation on DNA. These genes are reactivated by treatment with azacytidine, an inhibitor of DNA (cytosine-5)-methyltransferases. Methylation of cytosine-guanine dinucleotides (CpGs) on DNA is an important epigenetic mechanism involved in the selective regulation of gene expression and in the stabilization of chromatin, thus controlling tissue development and pathogenesis. Aberrant CpG methylation of specific genes is often found in many tumors and tumorigenic cell lines (15).Besides its role as inhibitor of collagen cross-linking, Hcys is also known to play a role in epigenetic gene regulation being directly involved in the DNA methylation process. Hcys represents a methyl group carrier involved in the S-adenosylmethionine-S-adenosylhomocysteine methylation cycle. Here, Hcys is remethylated to methionine, which is further activated to S-adenosylmethionine, the methyl donor in DNA methylation. S-Adenosylmethionine converts to S-adenosylhomocysteine after DNA methylation. Hydrolysis of S-adenosylhomocysteine to homocysteine completes the cycle (16).

show abstract

Section: Discussionmentioning

confidence: 99%

Homocysteine Suppresses the Expression of the Collagen Cross-linker Lysyl Oxidase Involving IL-6, Fli1, and Epigenetic DNA Methylation

Thaler

Agsten

Spitzer

et al. 2011

Journal of Biological Chemistry

107

View full text Add to dashboard Cite

show abstract

“…The activation of NFjB can originate from multiple surface receptors including Toll like receptors (TLR) or tumor necrosis factor a (TNFa) receptor (TNF-R1) that will ultimately result in cytokine production, such as IL-6 production. Interestingly, IL-6 can drive epigenetic loss of RASSF1A via DNA methyltransferase 1 (DNMT1) up-regulation [135,136] suggesting that inflammation can drive expression loss of RASSF1A and may explain why UC patients have epigenetic loss of RASSF1A. Importantly, IBD patients show an increased likelihood of developing colorectal cancer later in life and RASSF1A promoter methylation has been observed in colorectal cancers, suggesting that RASSF1A loss may be an early event in colorectal cancer development [131].…”

Section: Epigenetic Regulation Of the Rassfsmentioning

confidence: 99%

RASSF tumor suppressor gene family: Biological functions and regulation

et al. 2014

View full text Add to dashboard Cite

a b s t r a c tGenetic changes through allelic loss and nucleic acid or protein modifications are the main contributors to loss of function of tumor suppressor proteins. In particular, epigenetic silencing of genes by promoter hypermethylation is associated with increased tumor severity and poor survival. The RASSF (Ras association domain family) family of proteins consists of 10 members, many of which are tumor suppressor proteins that undergo loss of expression through promoter methylation in numerous types of cancers such as leukemia, melanoma, breast, prostate, neck, lung, brain, colorectal and kidney cancers. In addition to their tumor suppressor function, RASSF proteins act as scaffolding agents in microtubule stability, regulate mitotic cell division, modulate apoptosis, control cell migration and cell adhesion, and modulate NFjB activity and the duration of inflammation. The ubiquitous functions of these proteins highlight their importance in numerous physiological pathways. In this review, we will focus on the biological roles of the RASSF family members and their regulation.

show abstract

“…Monitoring of IL-6 serum levels also reflects the clinical response to steroid treatment and predicts clinical relapse after steroid-induced remission [41,42]. Additionally, a polymorphism within the IL-6 gene locus has been associated with early onset CD and persistent activation of the IL-6 signaling pathway is associated with the development of colorectal cancer [43,44,45,46]. Due to these observations IL-6 is regarded to be a promising target for the treatment of IBD.…”

Section: Anti Interleukin-6 Strategiesmentioning

confidence: 99%

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

Scharl

Vavricka²,

Rogler

2013

CDT

View full text Add to dashboard Cite

Significant advances have been achieved in the understanding of the pathogenesis of inflammatory bowel disease (IBD). A number of susceptibility genes have been detected by large genome wide screening-approaches. New therapeutic concepts emerge from these insights. The most important progress in recent years certainly is the introduction of biologics in the therapy of IBD. TNF blockers have been shown to be very effective for the control of complicated disease courses. Currently, in addition to the three already established anti-TNF antibodies, new anti-TNF molecules, for example Golimumab, are in clinical trials and also reveal promising results. However, not all of the patients respond to anti-TNF treatment and many patients lose their response. Therefore, additional therapeutic approaches are urgently needed. Attractive therapy targets are cytokines as well as their receptors and signaling pathways. At the moment a large number of biologicals and inhibitors are tested in clinical trials and some of them provide very promising results for the treatment of IBD patients. In particular, inhibition of IL-12p40 by specific antibodies as well as of the janus kinase (JAK)3 by a small molecule promise to be very effective approaches. Though antibodies targeting for example IL-6, IL-6R, IL-13 or CCR9 are only in the early steps of clinical development, they have already demonstrated to be a possible treatment option which needs to be confirmed in further trials. Taken together a large number of new therapeutic anti-cytokine approaches are currently tested in clinical trials in IBD patients. In this review, the new therapeutic approaches for cytokine inhibition in IBD patients are discussed. Taken together a large number of new therapeutic anti-cytokine approaches are currently tested in clinical trials in IBD patients. In this review, the new therapeutic approaches for cytokine inhibition in IBD patients are discussed.

show abstract

Upregulation of DNA Methyltransferase–Mediated Gene Silencing, Anchorage-Independent Growth, and Migration of Colon Cancer Cells by Interleukin-6

Cited by 138 publications

References 37 publications

Homocysteine Suppresses the Expression of the Collagen Cross-linker Lysyl Oxidase Involving IL-6, Fli1, and Epigenetic DNA Methylation

Homocysteine Suppresses the Expression of the Collagen Cross-linker Lysyl Oxidase Involving IL-6, Fli1, and Epigenetic DNA Methylation

RASSF tumor suppressor gene family: Biological functions and regulation

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

Contact Info

Product

Resources

About