Klotho, an anti-senescence related gene, is frequently inactivated through promoter hypermethylation in colorectal cancer

Abstract

The potential anti-senescence gene Klotho (KL) has been recently found to participate in the progression of several different human cancers including breast, lung, and cervical cancer. In this current study, we identified KL as a candidate tumor suppressor gene silenced through promoter hypermethylation in colorectal cancer (CRC). KL gene expression is found to be absent or reduced in colon cancer cell lines (5/6, 83.3%), which can be reversed by treatment with demethylation agent 5-aza-2'-deoxycytidine (Aza), but not HDAC inhibitor trichostatin A. In addition, KL expression is markedly downregulated in colorectal carcinoma tissues when compared to the adjacent nontumor tissues (n=25, p<0.001). The methylation of the KL gene promoter was frequently detected in primary tumor tissues (34/40, 85%) when compared with adjacent nontumor colon tissues. Furthermore, ectopic expression of KL led to the cell proliferation inhibition of colon cancer cell lines via the induction of cell apoptosis and S-phase cell cycle arrest. Taken together, our results suggest that KL is inactivated through promoter hypermethylation and potentially functions as a tumor suppressor gene in CRC.

Promoter methylation and age-related downregulation of Klotho in rhesus monkey

“…With an average increase of 1.8% at the six individually significant CpGs, the change in % methylation at any of these CpGs is modest. These results are not as profound as those observed in cancer where complete absence of KL is accompanied by hypermethylation across the KL promoter Pan et al 2011). However, in this study, we compared the methylation status of young and old brain during nonpathological aging where effects are not anticipated to be as dramatic as those in a pathological condition.…”

“…Hypermethylation of the KL promoter in cervical cancer and colon cancer eliminates KL expression Pan et al 2011). Since increased methylation is observed at the promoters of some age-downregulated genes (Hernandez et al 2011;Siegmund et al 2007), promoter methylation with age was assessed in rhesus monkey brain.…”

“…Likewise, DNA methyltransferases modify cytosine residues in CpG motifs, and such modification to GCrich promoters is more likely to occur with age (Christensen et al 2009;Hernandez et al 2011). In cervical carcinoma and colon cancer, the promoter of KL can be hypermethylated, particularly, in the late stages of disease and hypermethylation decreases KL expression Pan et al 2011). We hypothesized that age-related decreases in KL mRNA and protein were the result of epigenetic modification (i.e., oxidation and/or methylation) to the KL promoter.…”

Klotho inhibits human follicular thyroid cancer cell growth and promotes apoptosis through regulation of the expression of stanniocalcin-1

“…Mice deficient in Klotho expression exhibit increased renal gene expression of STC1 and STC2 compared with wild-type mice (19). Moreover, the level of Klotho was found to be downregulated in breast, lung, colon, pancreatic, gastric and cervical cancer (36)(37)(38). Although evidence suggests that Klotho acts as a tumor suppressor in numerous cancers (39), little is known concerning its potential effect on thyroid cancer.…”

The relevance of α-KLOTHO to the central nervous system: Some key questions

“…This phenomenon has been suggested to underlie the tightly controlled tissue-specific pattern of α-Klotho expression (Azuma et al, 2012) and is reported to increase with age (King et al, 2012). Interestingly, increased KL promoter methylation has also been described in a number of cancers, including cervical carcinoma, colorectal, breast and gastric cancers Pan et al, 2011;Rubinek et al, 2012;Wang et al, 2011). Fascinatingly, promoter methylation may be important to our observations.…”