Methylation of ASC/TMS1, a proapoptotic gene responsible for activating procaspase-1, in human colorectal cancer

Yokoyama, Taro; Sagara, Junji; Guan, Xin; Masumoto, Junya; Takeoka, Michiko; Komiyama, Yuichi; Miyata, Kazuyuki; Higuchi, Kaori; Taniguchi, Shun’ichiro

doi:10.1016/j.canlet.2003.08.027

Cited by 52 publications

(35 citation statements)

References 23 publications

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“…The same scenario applies to the measurement of ASC protein changes associated with ASC methylation. However, we have already been able to confirm that a decrease in ASC protein expression is associated with increased methylation [11,29]. Also, the exercise period in this study was 6 months, but a one year regime may be more revealing of the effects of interval walking since other unknown factors may have affected ASC methylation in the current experiment.…”

Section: Discussionmentioning

confidence: 54%

“…ASC gene expression is recognized to be modified epigenetically, i.e. is down regulated by the methylation of its CpG island surrounding exon 1, and the methylation was inversely correlated with ASC protein expression [11,29]. Here, we investigated how ASC activity is epigenetically influenced by age or chronic moderate exercise by assessing the methylation of the CpG islands in the ASC gene using bisulfate genomic sequencing methods.…”

Section: Introductionmentioning

confidence: 99%

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Exercise Effects on Methylation ofASCGene

et al. 2010

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Chronic moderate exercise has been reported to reduce pro-inflammatory cytokines. To analyze the molecular mechanisms by which training exerts these effects, the epigenetic influences of age and exercise on the ASC gene, which is responsible for IL-1β and IL-18 secretion, were investigated by ASC gene methylation. Further, the relationship between carcinogenesis and exercise, methylation of the p15 tumor suppressive gene was analyzed as well. High-intensity interval walking exercise, consisting of 3-minute low-intensity walking at 40% of peak aerobic capacity followed by a 3-minute high-intensity walking period above 70% of peak aerobic capacity, was continued for 6 months. Peripheral blood DNA extracts from young control (n=34), older control (n=153), and older exercise (n=230) groups were then analyzed by pyrosequencing for DNA methylation. Methylation of ASC decreased significantly with age (young control vs. older control, p<.01), which is indicative of an age-dependent increase in ASC expression. Compared to the older control group, the degree of ASC methylation was higher in the older exercise group (older control vs. older exercise:, p<.01) and presumably lower ASC expression. Neither exercise nor age affected the methylation of the p15. In summary, chronic moderate exercise appears to attenuate the age-dependent decrease in ASC methylation, implying suppression of excess pro-inflammatory cytokines through reduction of ASC expression.

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Section: Discussionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Exercise Effects on Methylation ofASCGene

et al. 2010

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“…Given that genetic ablation of the cytosolic adaptor MyD88 rescued APC deficiency in the colon (30), the regulatory role of NLRP6 on signaling pathways mediated through MyD88 remains now to be assessed. Of note, clinical investigations revealed that NLRP6 expression and ASC methylation may represent unique molecular markers of carcinogenesis (31,32). Collectively, we provide evidence that NLRP6 is involved in maintenance of the integrity of the epithelial barrier, suggesting that continuous stimulation of NLRP6 may represent a promising therapeutical strategy in IBD and CRC.…”

Section: Discussionmentioning

confidence: 63%

Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury

Normand

Delanoye-Crespin

Bressenot

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

318

311

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The colonic epithelium self-renews every 3 to 5 d, but our understanding of the underlying processes preserving wound healing from carcinogenesis remains incomplete. Here, we demonstrate that Nod-like receptor pyrin domain-containing protein 6 (NLRP6) suppresses inflammation and carcinogenesis by regulating tissue repair. NLRP6 was primarily produced by myofibroblasts within the stem-cell niche in the colon. Although NLRP6 expression was lowered in diseased colon, NLRP6-deficient mice were highly susceptible to experimental colitis. Upon injury, NLRP6 deficiency deregulated regeneration of the colonic mucosa and processes of epithelial proliferation and migration. Consistently, absence of NLRP6 accelerated colitis-associated tumor growth in mice. A gene-ontology analysis on a whole-genome expression profiling revealed a link between NLRP6 and self-renewal of the epithelium. Collectively, the integrity of the epithelial barrier is preserved by NLRP6 that may be manipulated to develop drugs capable of preventing adenoma formation in inflammatory bowel diseases.colonic myofibroblasts | colorectal cancer

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“…TMS1 was also independently identified by Masumoto et al (1999) as a protein that forms cytoplasmic 'specks' during retinoic acid induced differentiation or drug-induced apoptosis in HL60 cells, and called ASC. Subsequent studies by our lab and others have implicated the epigenetic silencing of TMS1 in a number of other tumor types, including melanomas, glioblastomas, non-small cell lung cancers, gastric and colorectal cancers (Moriai et al, 2002;Guan et al, 2003;Virmani et al, 2003;Yokoyama et al, 2003;Stone et al, 2004). Ectopic expression of TMS1 suppresses the growth of breast cancer cells, consistent with a role in tumor suppression (Conway et al, 2000).…”

Section: Introductionmentioning

confidence: 81%

“…TMS1 is a novel tumor suppressor gene that is subject to frequent epigenetic silencing in several different tumor types, including breast, gliomas, melanomas and nonsmall cell lung cancers, however the mechanism by which TMS1 silencing promotes carcinogenesis is not well understood (Conway et al, 2000;Moriai et al, 2002;Guan et al, 2003;Virmani et al, 2003;Yokoyama et al, 2003;Stone et al, 2004). Here, we examined the role of TMS1 in the cellular response of breast epithelial cells and human fibroblasts to death receptor activation and DNA damaging agents.…”

Section: Discussionmentioning

confidence: 99%