Interleukin 6 Supports the Maintenance of p53 Tumor Suppressor Gene Promoter Methylation

Abstract

A strong association exists between states of chronic inflammation and cancer, and it is believed that mediators of inflammation may be responsible for this phenomenon. Interleukin 6 (IL-6) is an inflammatory cytokine known to play a role in the growth and survival of many types of tumors, yet the mechanisms employed by this pleomorphic cytokine to accomplish this feat are still poorly understood. Another important factor in tumor development seems to be the hypermethylation of CpG islands located within the promoter regions of tumor suppressor genes. This common epigenetic alteration enables tumor cells to reduce or inactivate the expression of important tumor suppressor and cell cycle regulatory genes. Here we show that in the IL-6-responsive human multiple myeloma cell line KAS 6/1, the promoter region of p53 is epigenetically modified by methyltransferases, resulting in decreased levels of expression. Furthermore, cells treated with IL-6 exhibit an increase in the expression of the DNA maintenance methylation enzyme, DNMT-1. The DNA methyltransferase inhibitor zebularine reverses the methylation of the p53 promoter, allowing the resumption of its expression. However, when zebularine is withdrawn from the cells, the reestablishment of the original CpG island methylation within the p53 promoter does not occur in the absence of IL-6, and cells which do not receive IL-6 eventually die, as p53 expression continues unchecked by remethylation. Interestingly, this loss of viability seems to involve not the withdrawal of cytokine, but the inability of the cell to resilence the promoter. Consistent with this model, when cells that express IL-6 in an autocrine fashion are subjected to identical treatment, p53 expression is reduced shortly after withdrawal of zebularine. Therefore, it seems IL-6 is capable of maintaining promoter methylation thus representing one of the possible mechanisms used by inflammatory mediators in the growth and survival of tumors. (Cancer Res 2005; 65(11): 4673-82)

Global and gene‐specific promoter methylation changes are related to anti‐B[a]PDE‐DNA adduct levels and influence micronuclei levels in polycyclic aromatic hydrocarbon‐exposed individuals

“…The inflammatory cytokine IL-6 is fundamental in the formation and maintenance of p53 promoter methylation (via DMNT1 activation): its hypermethylation silences IL-6, reversing the methylation of the p53 promoter and allowing the resumption of its expression. 13 In conclusion, our results support the premise that chronic PAH exposure induces gene-specific (p53 and HIC1) and global (extrapolated from Alu and LINE-1 repeats) DNA methylation changes, while excluding other possible confounding factors. Our findings indicate that these epigenetic modifications are detectable in PBLs and are related to anti-B[a]PDE-DNA adduct and MN produced by PAH exposure in the same subject's PBLs.…”

“…12 Moreover, p53 can be epigenetically modulated by the inflammatory cytokine IL-6, via DNA methyltransferase (DNMT) activation. 13 Global DNA hypermethylation following in vitro chronic exposure to B[a]P was recently revealed in mouse embryonic fibroblasts and was associated to mutation as a consequence of genetic instability. 14,15 PBLs, although not considered target cells for PAH(B[a]P)-induced lung tumorigenesis, can be easily obtained from human subjects and their genetic (PAH(B[a]P)-DNA adducts) and epigenetic alterations (methylation) are correlated with levels in target tissues (e.g., lung).…”

DNMT3A and DNMT3B mediate autocrine hGH repression of plakoglobin gene transcription and consequent phenotypic conversion of mammary carcinoma cells

“…However, little is known regarding regulation of DNMTs by trophic or oncogenic factors and the underlying signalling mechanisms mediating DNMT expression and aberrant methylation patterns in cancer. Aberrant DNA methylation has been reported to affect many cellular processes, including transcriptional regulation (Herman, 1999), differentiation (Cameron et al, 1999) and apoptosis (Hodge et al, 2005). In the present study, we have demonstrated that autocrine hGHstimulated EMT in mammary carcinoma cells is executed by DNMT3A-and DNMT3B-mediated hypermethylation of the plakoglobin promoter.…”

“…In the present study, we have demonstrated that autocrine hGHstimulated EMT in mammary carcinoma cells is executed by DNMT3A-and DNMT3B-mediated hypermethylation of the plakoglobin promoter. Autocrine interleukin-6 (IL-6) has been reported to stimulate the expression and activity of DNMT1 (Hodge et al, 2001), and recently demonstrated to repress p53 gene transcription by hypermethylation of its promoter region in a human multiple myeloma cell line (Hodge et al, 2005). Autocrine IL-6 production in cholangiocarcinoma cells also produced resistance to the inhibitory effects of AZA on cell proliferation and soft agar colony formation (Wehbe et al, 2006) associated with altered promoter methylation of several genes.…”

Changes in saliva interleukin-6 levels in patients with oral squamous cell carcinoma

“…It is believed that proinflammatory cytokines play an important role in carcinogenesis. 8,26,27 and IL-6 inactivates p53 tumor suppressor gene. 26 Prior to this study, we expected that the levels of IL-6 would decrease rapidly after treatment of cancer.…”