Epigenetic regulation of the human telomerase reverse transciptase gene: A potential therapeutic target for the treatment of leukemia (Review)

Abstract

Telomerase activation is a critical step in human carcinogenesis through the maintenance of telomeres. Telomerase activity is primarily regulated by the human telomerase reverse transcriptase gene (hTERT), thus, an improved understanding of the transcriptional control of hTERT may provide potential therapeutic targets for the treatment of leukemia and other forms of cancer. Epigenetic modulation, a significant regulatory process in cell biology, has recently been shown to be involved in the regulation of the hTERT gene. Moreover, several epigenetic modifiers, including DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, are now in pre- and early clinical trials of leukemia as monotherapies or in combination with other drugs, and have achieved significant clinical success. In the present review, the epigenetic mechanisms associated with telomerase activity in leukemia, and the therapeutic potential of an antitelomerase strategy that combines epigenetic modifiers with telomerase hTR subunit small molecule inhibitors are discussed.

Keywords: epigenetic; human telomerase reverse transcriptase; leukemia.

Figure 1.

Chemical structures of selected (A) DNMT inhibitors and (B) HDAC inhibitors. DNMT, DNA methyltransferase; HDAC, histone deactylase.

Figure 2.

Complex molecular mechanisms and biological effects of hTERT. Epigenetic modification may affect hTERT expression and will form a permissive or inhibitive condition for hTERT transcription, depending on the specific cellular context. The suppression of hTERT promotes growth inhibition, differentiation, apoptosis and anti-angiogenesis. hTERT, human telomerase reverse transcriptase; HDAC, histone deacetylase; HDACI, HDAC inhibitor.

Figure 3.

A hypothesis is associated with antitelomerase strategy. The antitelomerase strategy, created by combining epigenetic modifiers with telomerase hTR subunit small molecule inhibitors (such as SOT-095), may exert a more potent effect for the treatment of human leukemia, since each approach is able to individually inhibit telomerase activity. hTERT, human telomerase reverse transcriptase.