In brief

Oncogenic mutations trigger an uptick in the levels of a protein called JunD, which activates a cascade of molecular events that lead to tumour formation.

© Unsplash

How cancer seizes the immortality gene

21 Apr 2023

Researchers have discovered a molecular pathway in colorectal cancer cells that leads to uncontrolled division, creating an avenue for more targeted therapies.

Deep within every cell in the body lies the key to immortality: an enzyme called human telomerase reverse transcriptase (hTERT). Cancer cells have a way of activating the hTERT enzyme, which unlocks the door to limitless self-renewal.

An estimated 90% of human cancer cells feature changes to the gene regulators that turn on hTERT, making them high-value therapeutic targets to combat cancer. “These regulatory regions are mainly activated in a disease-specific manner, providing unique patterns that differ from healthy cells,” said Vinay Tergaonkar, a Senior Principal Investigator and Director of the Cancer Signalling and Therapies division at A*STAR’s Institute of Molecular and Cell Biology (IMCB).

The many molecular events that converge to ignite hTERT and initiate tumour growth have, however, eluded scientists. For instance, the origins of some cancers can be traced back to a faulty hTERT gene promoter, but Tergaonkar said that’s only part of the story.

“The stepwise progression of colorectal cancer and the mutations that initiate tumour growth are well-established, but the hTERT reactivation mechanism was the missing piece of the puzzle,” he explained.

Tergaonkar and colleagues put the dynamics of hTERT reactivation in the spotlight using a colorectal cancer model created from patient-derived colorectal cancer cell lines.

The researchers discovered that mutations in the APC and KRAS genes spiked levels of a protein called JunD, which unravelled the DNA helix to expose the hTERT gene promoter region. These changes preceded hTERT activation and provided insights into the molecular cascades that culminate in tumour formation.

hTERT is active during embryonic development and inactivated once stem cells differentiate, which is why most normal adult cells have a fixed life span. “Cancer cells escape from this by reactivating hTERT and continue to proliferate indefinitely,” said Tergaonkar, adding that the team’s findings likely apply to other cancer types, including gastric and lung cancers.

Systemic hTERT inhibitor drugs currently in development can cause debilitating side effects in patients. Tergaonkar said that the group is now on the hunt for next-generation inhibitors against targets involved in hTERT reactivation, in particular those that are gentler and more effective.

“We are generating reporter systems to perform high-throughput screens to identify molecules that can selectively inhibit cancer-cell proliferation,” said Tergaonkar. “Hopefully, some will go to clinical trials.”

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB) and the Genome Institute of Singapore (GIS).

Want to stay up to date with breakthroughs from A*STAR? Follow us on Twitter and LinkedIn!


Akıncılar, S.C., Chua, J.Y.H., Ng, Q.F., Chan, C.H.T., Eslami-S, Z., et al. Identification of mechanism of cancer-cell-specific reactivation of hTERT offers therapeutic opportunities for blocking telomerase specifically in human colorectal cancer. Nucleic Acids Research, gkac479 (2022). | article

About the Researchers

Vinay Tergaonkar obtained his PhD (2001) from NCBS Bangalore through an international cancer society (UICC) fellowship for collaborative research at Tufts University, Boston, USA. He has been a fellow (2001-2004) and a special fellow (2004-present) of the Leukemia and Lymphoma Society of America and conducted his postdoctoral studies at the Salk Institute for Biological Studies, La Jolla, California. He currently serves as Research Director at A*STAR's Institute of Molecular and Cell Biology (IMCB) and Professor at the School of Medicine at the National University of Singapore. He serves on the Editorial Boards of 1) Science Advances (AAAS), 2) Molecular and Cellular Biology (American Society for Molecular Biology), 3) Biochemical Journal (Portland Press). Work from his lab has received international recognition including the British council development award (2014), the Premiers’ fellowship from Government of South Australia (2015) and University of Macau Distinguished Professorship (2019).
As a SINGA award recipient, Semih AKINCILAR received his PhD in Biochemistry from the National University of Singapore in 2017 He was awarded an OF-YIRG grant in 2018 to study the role of lncRNAs in inflammation and secured an industrial GAP fund and co-founded Denome Technologies, a startup focusing on developing gene expression-based disease prediction algorithms. His research focuses mainly on the epigenetic regulation of signaling pathways in human disorders. He spent significant time understanding how telomerase is reactivated in 90% of cancer cells to provide infinite proliferation capability. He has identified several novel genomic regions critical for telomerase expression and filed a patent and several technology disclosures. His research interest is understanding how the non-coding genome regulates chronic inflammation and participates in cancer progression.

This article was made for A*STAR Research by Wildtype Media Group