TERT Promoter Mutations and Telomerase in Melanoma

Abstract

Malignant melanoma is an extremely malignant tumor with a high mortality rate and an increasing incidence with a high mutation load. The frequency of mutations in the TERT promoter exceeds the frequency of any known noncoding mutations in melanoma. A growing number of recent studies suggest that the most common mutations in the TERT promoter (ATG start site -124C>T and -146C>T) are associated with increased TERT mRNA expression, telomerase activity, telomere length, and poor prognosis. Recently, it has been shown that TERT promoter mutations are more correlated with the occurrence, development, invasion, and metastasis of melanoma, as well as emerging approaches such as the therapeutic potential of chemical inhibition of TERT promoter mutations, direct telomerase inhibitors, combined targeted therapy, and immunotherapies. In this review, we describe the latest advances in the role of TERT promoter mutations and telomerase in promoting the occurrence, development, and poor prognosis of melanoma and discuss the clinical significance of the TERT promoter and telomerase in the treatment of melanoma.

Figure 1

The percentage of the major mutations in melanoma. (a) Cutaneous melanoma. (b) Mucosal melanoma. (c) Acral melanoma.

Figure 2

The mechanisms of TERT promoter mutations in occurrence, development, invasion, and therapeutic potentials in melanoma. The wild-type TERT promoter is enriched with repressive histone marks such as H3K27me3. In the context of C250T TERT promoter mutation, a proximal ETS binding motif is created next to a p52 half-site, which facilitates cooperative binding of ETS1 and p52. Next, during deregulated noncanonical NFκB signaling in C250T mutant cancers, stabilization of ETS-p52 dimer on mutant TERT promoter results in elevated TERT expression. The critical residues (in blue) required for dimerization of ETS and p52 are absent in both WT and C228T TERT promoters. C228T mutation will lead to an epigenetic switch that occurs resulting in the association of active H3K4me2/3 marks and GABP recruitment on the mutant allele. Stabilization of GABP on mutant TERT promoter leads to TERT reactivation. Besides, BRAF V600E/MAPK pathway phosphorylates and activates FOS, which in turn acts as a transcription factor to bind and activate the GABPB promoter, increasing the expression of GABPB and driving the formation of the GABPA-GABPB complex. The formation of the GABP complex selectively binds and activates the mutant TERT promoter, upregulating TERT expression. Next, TERT promoter mutations will increase TERT transcription activity. Telomerase activity mainly depends on the amount of TERT. Increased telomerase activity will maintain telomere length and promote cell immortalization and melanoma growth.