The rs1001179 SNP and CpG methylation regulate catalase expression in chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia (CLL) is an incurable disease characterized by an extremely variable clinical course. We have recently shown that high catalase ( CAT ) expression identifies patients with an aggressive clinical course. Elucidating mechanisms regulating CAT expression in CLL is preeminent to understand disease mechanisms and develop strategies for improving its clinical management. In this study, we investigated the role of the CAT promoter rs1001179 single nucleotide polymorphism (SNP) and of the CpG Island II methylation encompassing this SNP in the regulation of CAT expression in CLL. Leukemic cells harboring the rs1001179 SNP T allele exhibited a significantly higher CAT expression compared with cells bearing the CC genotype. CAT promoter harboring the T -but not C- allele was accessible to ETS-1 and GR-β transcription factors. Moreover, CLL cells exhibited lower methylation levels than normal B cells, in line with the higher CAT mRNA and protein expressed by CLL in comparison with normal B cells. Methylation levels at specific CpG sites negatively correlated with CAT levels in CLL cells. Inhibition of methyltransferase activity induced a significant increase in CAT levels, thus functionally validating the role of CpG methylation in regulating CAT expression in CLL. Finally, the CT/TT genotypes were associated with lower methylation and higher CAT levels, suggesting that the rs1001179 T allele and CpG methylation may interact in regulating CAT expression in CLL. This study identifies genetic and epigenetic mechanisms underlying differential expression of CAT , which could be of crucial relevance for the development of therapies targeting redox regulatory pathways in CLL. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00018-022-04540-7.

Hypermethylation of nc886 in HPV-positive oropharyngeal cancer and its clinical implications: An epigenome-wide association study

“… 58 CAT gene promoter contains several CpG islands and previous reports have implicated DNA methylation as a regulatory mechanism of CAT gene expression. 58 , 59 , 60 We found lower promoter methylation level of CAT gene in HPV(+) than HPV(−) OPSCC patients, indicating increased expression of catalase and elevated antioxidant activity, likely acting as a host defense mechanism against exogeneous HPV infection and tumor progression.…”

The Association of Oxidative Stress-Related Gene Polymorphisms with Pain-Related Temporomandibular Disorders and Oral Behavioural Habits

“…Some research reported that allele A of rs1001179 (CAT) was associated with a 0.6fold decrease in risk for acoustic neuroma [42]. Galasso et al [43] revealed the importance of the CAT rs1001179 polymorphism with respect to the CAT gene activity. In their model of investigation, leukemic cells harbouring the rs1001179 SNP T allele exhibited a significantly higher CAT expression than the cells bearing the CC genotype, due to the increased binding of two transcription factors, ETS proto-oncogene 1 (ETS-1) and glucocorticoid receptor beta (GR-β).…”

Association of Oxidative-Stress-Related Gene Polymorphisms with Pain-Related Temporomandibular Disorders and Oral Behavioural Habits

“…Some research reported that allele A of rs1001179 ( CAT ) was associated with a 0.6-fold decrease in risk for acoustic neuroma [ 42 ]. Galasso et al [ 43 ] revealed the importance of the CAT rs1001179 polymorphism with respect to the CAT gene activity. In their model of investigation, leukemic cells harbouring the rs1001179 SNP T allele exhibited a significantly higher CAT expression than the cells bearing the CC genotype, due to the increased binding of two transcription factors, ETS proto-oncogene 1 (ETS-1) and glucocorticoid receptor beta (GR-β).…”

“…In their model of investigation, leukemic cells harbouring the rs1001179 SNP T allele exhibited a significantly higher CAT expression than the cells bearing the CC genotype, due to the increased binding of two transcription factors, ETS proto-oncogene 1 (ETS-1) and glucocorticoid receptor beta (GR-β). The strength of binding and transcriptional activity of CAT was also dependent on the level of DNA methylation [ 43 ]. These data imply that even though minor alleles are more likely to be risk alleles in complex diseases, this may not always be the case [ 44 ].…”