Epigenetic suppression of human telomerase (hTERT) is mediated by the metastasis suppressor NME2 in a G-quadruplex-dependent fashion.
Transcriptional activation of the human telomerase reverse transcriptase (hTERT) gene, which remains repressed in adult somatic cells, is critical during tumorigenesis. Several transcription factors and the epigenetic state of the hTERT promoter are known to be important for tight control of hTERT in normal tissues, but the molecular mechanisms leading to hTERT reactivation in cancer are not well-understood. Surprisingly, here we found occupancy of the metastasis suppressor non-metastatic 2 (NME2) within the hTERT core promoter in HT1080 fibrosarcoma cells and HCT116 colon cancer cells and NME2-mediated transcriptional repression of hTERT in these cells. We also report that loss of NME2 results in up-regulated hTERT expression. Mechanistically, additional results indicated that the RE1-silencing transcription factor (REST)-lysine-specific histone demethylase 1 (LSD1) co-repressor complex associates with the hTERT promoter in an NME2-dependent way and that this assembly is required for maintaining repressive chromatin at the hTERT promoter. Interestingly, a G-quadruplex motif at the hTERT promoter was essential for occupancy of NME2 and the REST repressor complex on the hTERT promoter. In light of this mechanistic insight, we studied the effects of G-quadruplex-binding ligands on hTERT expression and observed that several of these ligands repressed hTERT expression. Together, our results support a mechanism of hTERT epigenetic control involving a G-quadruplex promoter motif, which potentially can be targeted by tailored small molecules.
['Saha|Dhurjhoti|D|', 'Singh|Ankita|A|', 'Hussain|Tabish|T|', 'Srivastava|Vivek|V|', 'Sengupta|Suman|S|', 'Kar|Anirban|A|', 'Dhapola|Parashar|P|', 'Dhople|Vishnu|V|', 'Ummanni|Ramesh|R|', 'Chowdhury|Shantanu|S|']
D019943:Amino Acid Substitution D002277:Carcinoma D045744:Cell Line, Tumor D002478:Cells, Cultured D047369:Chromatin Immunoprecipitation D063185:Epigenetic Repression D005354:Fibrosarcoma D054856:G-Quadruplexes D017930:Genes, Reporter D056466:Histone Demethylases D006801:Humans D016297:Mutagenesis, Site-Directed D054778:NM23 Nucleoside Diphosphate Kinases D009363:Neoplasm Proteins D017354:Point Mutation D011401:Promoter Regions, Genetic D055503:Protein Multimerization D034622:RNA Interference D011994:Recombinant Proteins D012097:Repressor Proteins D019098:Telomerase
epigenetics NME2 G-quadruplex REST repressor complex chromatin modification telomerase reverse transcriptase (TERT) transcription regulation