DNA hypermethylation within TERT promoter upregulates TERT expression in cancer

Abstract

Of the 1352 samples in the cohort, which were provided by multiple collaborators, four samples of breast tissue for which DNA was analyzed were a part of another study. Since these samples did not go through the same rigorous screening process, including pathology review and extraction of DNA from paraffin tissues, that was applied to all other samples, the authors are less confident in their exact identity and have decided to retract them from the study. This does not change the message of the paper, but results in changes in and in one pie chart in Figure 2E, that for breast cancer. The corrected figure parts are below. In addition, the supplemental material containing sample information has been updated online.

Complex context relationships between DNA methylation and accessibility, histone marks, and hTERT gene expression in acute promyelocytic leukemia cells: perspectives for all‐trans retinoic acid in cancer therapy

“…Our previous study performed on APL cell lines identified two distinct functional domains in hTERT promoter, one distal and one proximal, differentially methylated (Azouz et al , 2010). These results are in agreement with the recent identification of the TERT hypermethylation oncologic region, a 433‐bp genomic region located −159 to −591 bp upstream the TSS (Castelo‐Branco et al , 2016; Leao et al , 2019; Lee et al , 2019), as a potential biomarker in several cancers. This region is of major importance, because its methylation status correlates with hTERT expression.…”

Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

“…Therefore, a close genomic-epigenetic interaction is required for telomerase activation, like TPE-OLD-mediated TERT transcription. Interestingly, TERT promoter methylation is required for cancer cells to activate TERT transcription, while TERT induction in turn promotes the aberrant methylation by upregulating the expression of DNA methyltransferases, which forms a positive feedback loop [20,23].…”

“…2) [21,22]. The TERT harbors a single promoter embedded in a CpG island (−1800 to +2300 relative to ATG), while the proximal core promoter is within a 330 bp upstream and 37 bp downstream from ATG (−330 to +37) [23][24][25][26]. Remarkably, the TERT promoter region is rich with biding motifs for multiple transcription factors including the MYC oncogene (E-box) and Sp1 (GC box), but lack TATA and CAAT boxes [21,27].…”

“…On the other hand, the promoter also carries sites for repressor binding. Another unique feature is that the TERT promoter is unmethylated in normal human cells, whereas methylated in malignant cells, and Lee et al identified the 52 CpG-containing TERT hypermethylated oncological region (THOR) as a cancer-associated epigenetic mechanism of TERT upregulation [23][24][25][26]. Several lines of evidence suggest that the unmethylated promoter sequence favors a repressor-binding [23].…”

“…DNA methylation, histone acetylation, methylation, and phosphorylation have all been shown to be involved in the TERT transcription regulation [31,32,42,45,46]. The TERT promoter is in general unmethylated in normal cells, while its methylation is required for TERT expression and telomerase activation in cancer cells [23][24][25][26]. Histone acetylation/deacetylation was shown to be a common underlying feature to TERT transactivation/repression in human cells [31,32,42,45].…”