The regulations of telomerase reverse transcriptase (TERT) in cancer

Abstract

Abnormal activation of telomerase occurs in most cancer types, which facilitates escaping from cell senescence. As the key component of telomerase, telomerase reverse transcriptase (TERT) is regulated by various regulation pathways. TERT gene changing in its promoter and phosphorylation respectively leads to TERT ectopic expression at the transcription and protein levels. The co-interacting factors play an important role in the regulation of TERT in different cancer types. In this review, we focus on the regulators of TERT and these downstream functions in cancer regulation. Determining the specific regulatory mechanism will help to facilitate the development of a cancer treatment strategy that targets telomerase and cancer cell senescence. As the most important catalytic subunit component of telomerase, TERT is rapidly regulated by transcriptional factors and PTM-related activation. These changes directly influence TERT-related telomere maintenance by regulating telomerase activity in telomerase-positive cancer cells, telomerase assembly with telomere-binding proteins, and recruiting telomerase to the telomere. Besides, there are also non-canonical functions that are influenced by TERT, including the basic biological functions of cancer cells, such as proliferation, apoptosis, cell cycle regulation, initiating cell formation, EMT, and cell invasion. Other downstream effects are the results of the influence of transcriptional factors by TERT. Currently, some small molecular inhibitors of TERT and TERT vaccine are under research as a clinical therapeutic target. Purposeful work is in progress.

As the most important catalytic subunit component of telomerase, TERT is rapidly regulated by transcriptional factors and PTM-related activation. These changes directly influence TERT-related telomere maintenance by regulating telomerase activity in telomerase-positive cancer cells, telomerase assembly with telomere-binding proteins, and recruiting telomerase to the telomere. Besides, there are also non-canonical functions that are influenced by TERT, including the basic biological functions of cancer cells, such as proliferation, apoptosis, cell cycle regulation, initiating cell formation, EMT, and cell invasion. Other downstream effects are the results of the influence of transcriptional factors by TERT. Currently, some small molecular inhibitors of TERT and TERT vaccine are under research as a clinical therapeutic target. Purposeful work is in progress.

Fig. 1. Activators and inhibitors targeting telomerase reverse transcriptase (TERT), involved in regulating telomerase activity.

The activators include NVL2 and EST1 lengthen telomere by influencing telomerase holoenzyme assembly and activating telomerase, respectively. Some inhibitors such as PinX1, MCRS2, and PML inhibit telomerase activity through unknown mechanism. MKRN1 influences protein stability of TERT and decreases telomerase activity eventually. PIF1 could prevent the combination of telomerase with long telomere ends which leads to telomere shortening. CST complex which combined with CTC1, TEN1, and STN1 could destroy the interaction of the telomere with TPP1-POT1 and also leads to telomere shortening.

Fig. 2. The transportation of TERT.

Transportation of TERT from the Cajal body to nuclear following telomerase construction due to Hsp90 and p23 through the activation of TCAB. Other factors participating in TERT translocations are described, and the interaction between TERT and shelterin complex is shown.

Fig. 3. Non-canonical TERT function in cancer regulation.

Instead of telomerase regulation, TERT also participate in proliferation, apoptosis, cell cycle controlling, tumor-initiating cell formation, EMT, cell invasion, and the regulation of transcriptional factor-related gene expression changing processes. These changings in cancer also influence the components in tumor microenvironment.