DNMT inhibition
Description
Introduction: Telomerase is reactivated in the majority of cancers. In gliomas, it is common that the TERT promoter is mutated. In this study, we investigated the proximal and distal TERT promoter, in terms of DNA methylation. Methods: We did bisulfite sequencing in zebrafish tissue samples for the distal tert promoter. Then performed site directed mutagenesis in TERT CpG islands in gliomas and silenced DNMT3B in glioma samples. Results: We identified a hypomethylation site in tert promoter in the zebrafish brain tissues, which was associated with aging and shortened telomeres. In human glioma samples, we found novel hotspots that abolish telomerase activity. Then, through silencing of DNMT3B, we induced senescence in glioma cells. Finally, we propose a model regarding the efficacy of two chemotherapeutic drugs, adriamycin and azacytidine, on gliomas. Discussion/Conclusion: Adriamycin is efficient in p53 positive cells, whereas azacytidine works well in p53 negative cells. However, DNMT3B inhibition is effective in inducing senescence independent of p53 status. Hence, we propose that DNMT3B silencing can be used as a therapeutic agent in gliomas.