The identification of an important cancer progression mechanism that is observed in 90% of cancer cells may help in the development of novel cancer specific drugs with potentially fewer side effects.

The discovery by scientists from A*STAR’s Institute of Molecular and Cell Biology (IMCB) and Genome Institute of Singapore (GIS), as well as the NUS Cancer Science Institute of Singapore (CSI Singapore), National Cancer Centre Singapore (NCCS) and Nanyang Technological University (NTU), was published in the on June 14, 2022 in journal Nucleic Acid Research.

The life span of a normal, healthy, cells is determined by telomeres, protective caps at the ends of chromosomes. Each time a cell divides, the telomeres become shorter until eventually, they are too short to protect the DNA and the cell dies naturally. In contrast, cancer cells live through reactivating telomerase, an enzyme which can prolong telomeres, but is inactive in most adult cells.

By activating the Human Telomerase Reverse Transcriptase (hTERT) gene, cancer cells can continue to divide and multiply indefinitely in the body.

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While mutations in hTERT promoter present in 19% of cancers are recognized as key drivers of hTERT reactivation, mechanisms by which wildtype hTERT (WT-hTERT) promoter is reactivated, in majority of human cancers, has remained unknown for decades.

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Studies have shown that telomerase is reactivated in as much as 90% of cancers, making hTERT, through which telomerase is activated, an excellent candidate for targeting cancer cells.

Semih Akincilar, Senior Research Fellow at A*STAR’s Institute of Molecular and Cell Biology and lead researcher of the study, performing gene expression analysis. Image credit: Dorcas Hei, A*STAR’s Institute of Molecular and Cell Biology (IMCB). Photo courtesy: © 2022 Dorcas Hei, A*STAR’s Institute of Molecular and Cell Biology (IMCB)

Inhibiting telomerase
Current efforts to treat cancer by inhibiting telomerase with drugs have proven to be too toxic to patients due to the strong side effects on healthy cells.

The research team has identified a specific DNA structure known as Tert INTeracting region 2 (T-INT2), a critical chromatin region essential for reactivating WT-hTERT promoter in colorectal cancers. Elevated β-catenin and JunD level in colorectal cancer facilitates chromatin interaction between hTERT promoter and T-INT2 that is necessary to turn on hTERTexpression.

The discovered DNA structure forms only in cancer cells and brings the necessary molecular machinery into the correct position to activate the hTERT gene.

“Activation of telomerase is the most common oncogenic event providing immortality to cancer cells. We now know how to inhibit telomerase activity to target cancer cells specifically,” noted Semih Akincilar, Senior Research Fellow at A*STAR’s IMCB and lead researcher of the study.

Colorectal cancer
Patient-derived colorectal cancer cell lines generated by GIS were used to identify correlative gene expression for hTERT activation and ascertain the physiological relevance of the findings in this study. These models will serve as a testbed for future studies aimed at the development of cancer-specific inhibitors of telomerase.

Pharmacological screens uncovered salinomycin (Sal), a polyether ionophore antibiotic from Streptomyces albus, which has been proven to be able to kill different types of human cancer cells, most likely via interfering with ABC drug transporters, the Wnt/β-catenin signaling pathway, or other pathways.  The scientists found that salinomycin also inhibits JunD mediated hTERT-T-INT2 interaction that is required for the formation of a stable transcription complex on the hTERT promoter.

The results of the study demonstrated for the first time how known colorectal cancer alterations, such as APC, lead to WT-hTERT promoter reactivation during stepwise-tumorigenesis and provide a new perspective for developing cancer-specific drugs.

The researchers believe that the detailed mechanism of hTERT activation provided in this study is instrumental in designing new drugs to inhibit hTERT specifically in cancer cells with less side effects. By building on this work, the researchers will collaborate with industrial and clinical partners to develop cancer-specific telomerase inhibitors and bring those candidates to the clinical stage.

“This study will be a guide for developing next-generation cancer inhibitors,” Akincilar concluded.

Reference
[1] Akıncılar SC, Chua JYH, Ng QF, Chan CHT, Eslami-S Z, Chen K, Low JL, Arumugam S, Aswad L, Chua C, Tan IB, DasGupta R, Fullwood MJ, Tergaonkar V. Identification of mechanism of cancer-cell-specific reactivation of hTERT offers therapeutic opportunities for blocking telomerase specifically in human colorectal cancer. Nucleic Acids Res. 2022 Jun 14:gkac479. doi: 10.1093/nar/gkac479. Epub ahead of print. PMID: 35697349.

Featured image: Singapore. Photo cortesey: © 2020-2022 Zhu Hongzhi on Unsplash. Used with permission.

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