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Telomerase Reactivation in Aggressive Cancer Cells: Non‐duplex Structure formation is key to the Epigenetic State of the Telomerase promoter
Author(s) -
Sharma Shalu,
Mukherjee Ananda,
Roy Shuvra,
Bagri Sulochana,
Lier Silje,
Verma Meenakshi,
Sengupta Antara,
Kumar Manish,
Nesse Gaute,
Pandey Deo,
Chowdhury Shantanu
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02801
Subject(s) - telomerase , epigenetics , telomerase reverse transcriptase , telomere , cancer research , biology , cancer cell , dna methylation , promoter , cancer , microbiology and biotechnology , genetics , dna , gene expression , gene
Telomerase de‐regulation is long known to be one of the causal factors in cancer initiation and progression. It is repressed in adult normal cells and is known to be activated in ~90% of cancers. However underlying mechanisms that trigger reactivation have remained poorly understood. Our recent findings show the intriguing possibility that DNA secondary structure G‐quadruplex forms regulate the epigenetic state of the telomerase promoter, and thereby expression of telomerase remains under control. The relevance of this mechanism is underscored through two clinical mutations – found in high frequency in a large number of melanoma glioblastoma patients ‐ that disrupt G‐quadruplex formation. Ligand‐induced re‐stabilization of the promoter G‐quadruplex restored the epigenetic state and re‐suppressed telomerase in cancer cells, substantiating the newly revealed mechanistic understanding. Overall, this brings forth two novel points. First, shows the use of G‐quadruplex‐stabilizing ligands in regulating hTERT expression via restoration of the transcription factor binding site in neoplastic, hTERT‐ reactivated cancer cells. Second, it shows the possibility for development of novel G‐quadruplex targeting epigenetic drugs that may work in telomerase regulation.