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.”