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proposing for the first time that the hypermethylation of TERT promoter and the methylation of histone
H3-K9 resulted in the inhibition of c-Myc binding in E-box 1, which in turn inactivated TERT expression.
However, this result contrasts with previous studies, which showed that TERT promoter epigenetic
modification had either a positive correlation or no correlation with TERT expression and telomerase
activity in other cancer types [79-83] . A more recent study examining 125 HCC cases in the Han Chinese
population found that the promoter of the TERT gene is significantly hypermethylated, and it further showed
that the hypermethylation is associated with higher expression of TERT, suggesting that TERT promoter
hypermethylation contributes to the progression of liver carcinogenesis via elevating TERT expression
[84]
level . Overall, there is no definite conclusion regarding whether hypermethylation of TERT promoter has
a positive or negative correlation with TERT expression and telomerase activity.

MECHANISMS OF TERT PROMOTER MUTATIONS CONTRIBUTING TO THE DEVELOPMENT
OF HCC AND OTHER CANCERS
Although TERT promoter mutations are strongly associated with several cancers, the mechanism by which
TERT promoter mutations lead to cancer development is not fully understood. How TERT promoter
mutations increase TERT expression and whether the up-regulation of TERT directly translates into active
telomerase activity that eventually contributes to tumorigenesis are two important questions requiring
answers.

Mechanisms of TERT promoter in other cancers
It is currently accepted that C228T and C250T, the two most common mutation types in TERT promoter
region, both create an 11-bp binding motif (5’-CCCCTTCCGGG-3’) for E-twenty-six (ETS) transcription
factors [26,85,86] . In glioblastoma, a total of five ETS transcription factors were found (ELF1, ETS1, ETV3, ETV4
and GABPA) that modulate TERT expression. GABPA complexes with GABPB to form a fully functional
heterodimer GABP transactivator, it was the only factor that reproducibly regulated TERT expression
[24]
[86]
in a mutation-specific manner . Akincilar et al. , using cell lines from several cancer types, including
melanoma, glioblastoma, colon, and prostate cancers, etc., reported that TERT promoter mutations
enhanced the binding of GABPA, mediating long-range chromatin interaction (at chr5: 1,556,087-1,558,758,
a region 300 kb upstream of promoter), enrichment of active histone markers H3K4Me3 and H3K9Ac and
subsequent POL2 recruitment, thus driving TERT transcription. Another study suggested a slightly different
[85]
mechanism. According to work by Li et al. , the TERT promoter with C250T mutation was driven by NF-
κB signaling. On activation of this signaling pathway, p52 (NF-κB2) is recruited to the C250T region, but not
[85]
the C228T region, and cooperates with ETS factors ETS1/2 to drive efficient TERT transcription . TERT
promoter mutations are widely found together with BRAF V600E alteration in human cancers, particularly
in thyroid cancer and melanoma [87-92] . A recent study found that that TERT promoter mutations and BRAF
V600E cooperatively upregulated TERT expression and promoted the oncogenic behaviors in the papillary
[93]
thyroid cancer cells .
Mechanisms of TERT promoter mutations in HCC
[94]
TERT promoter mutation was a later oncogenic event. Pilati et al. have screened TERT promoter in a large
series of liver cancers including adenomas, borderline lesions hepatocellular adenomas (HCA)/HCC, HCC
derived from adenomas and classical HCC, and found TERT promoter mutations did not exist in classical
adenomas, but in borderline lesions HCA/HCC (17%) and HCC cases derived from adenomas (56%) which
frequency was similar to that in classical HCC (54%).

There are only a few studies focusing on the mechanism of how TERT promoter mutations influence TERT
expression and lead to malignant transformation of liver cells [Figure 1]. Telomerase activation is important
to maintaining telomere length that confers cancer cells infinite ability to overcome the proliferation barrier.
One study demonstrated that TERT mRNA expression and telomerase activity were higher in patients with