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VIEWS
1212 | CANCER DISCOVERY�NOVEMBER 2016 www.aacrjournals.org
Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, Texas .
Corresponding Author: Jerry W. Shay, The University of Texas Southwest-ern Medical Center, 5323 Harry Hines Boulevard, Dallas , Texas 75390-9039. Phone: 214-648-4201; Fax: 214-648-5814; E-mail: [email protected]
transcription factor family. The ETS family transcription
factors GABPA and ETS1 have been identifi ed as the binding
factor in most cancer cells with TERT promoter mutations ( 7,
8 ). A better understanding of what facilitates specifi c proxi-
mal promoter mutations in the TERT gene could provide
clues for developing therapeutic strategies to block telomer-
ase activation in most human cancers. In this issue of Cancer
Discovery , Ak ı nc ı lar and colleagues ( 2 ) demonstrate a novel
mechanism of mutant TERT promoter reactivation via long-
range chromatin interactions.
Taking advantage of CRISPR/Cas9 genome editing tech-
niques, Ak ı nc ı lar and colleagues ( 2 ) generated a series of
isogenic cancer cell lines with wild-type and mutant TERT pro-
moters. They showed that reversal of the mutant to wild-type
TERT promoter led to heterochromatin changes in the TERT
promoter region as well as reduction in telomerase activ-
ity. This observation is consistent with the previous report
that the mutant TERT promoter allele exhibits H3K4me2/3
(active chromatin histone mark) and recruits the GABPA
transcription factor, whereas the wild-type TERT allele retains
H3K27me3 (a repressed chromatin histone mark) and does
not recruit the GABPA transcription factor ( 9, 10 ). Because it
has been recently proposed that GABPA may have a potential
role in engaging long-range chromatin interactions, Ak ı nc ı lar
and colleagues investigated whether GABPA bound to the
mutant TERT promoter can engage long-range chromatin
interactions. They performed circular chromosome confor-
mation capture assays to test whether the three-dimensional
genome organization changed in the vicinity of the mutant
TERT promoter locus compared with wild-type TERT . Impor-
tantly, they found that mutant TERT promoters display
long-range chromatin interactions with a region 300 kb
upstream of the TERT promoter (chr5: 1,556,087–1,558,758),
and that these interactions are mediated by GABPA.
By performing additional genome-editing experiments,
they also showed that introducing a mutant sequence in the
wild-type TERT promoter could change long-range chroma-
tin interactions. Moreover, the acute depletion of GABPA by
using GABPA siRNA induced signifi cant reduction of long-
range chromatin interaction. These experiments indicate that
long-range chromatin interactions are reversible changes and
dependent on a single-nucleotide mutation sequence via
GABPA binding. The most striking part of this study is that
Ak ı nc ı lar and colleagues ( 2 ) generated knockout cell lines tar-
geting the interacting region (chr5: 1,556,087−1,558,758) far
from the TERT locus. The removal of the interacting region
reduced TERT expression and altered the epigenetic status
in the proximal TERT promoter region without any change
in GABPA expression. These experiments strongly support
the importance of the interaction between the proximal
TERT promoter and the chr5: 1,556,087−1,558,758 intergenic
region in driving mutant TERT promoter activity ( Fig. 1 ).
In summary, the report by Ak ı nc ı lar and colleagues ( 2 )
identifies a novel mechanism of TERT reactivation by
cancer-specifi c TERT promoter mutations that are mediated
by a long-range chromatin interaction between the TERT
promoter and a region 300 kb from the TERT promoter.
Targeting this long-range chromatin interaction exclusively
harbored in cancers with TERT promoter mutation may be
a potential therapeutic strategy for inhibiting telomerase
activity and the indefi nite cell proliferation that is one of
the hallmarks of cancer. However, there are additional
Figure 1. TERT promoter mutation reactivates the silenced TERT promoter via generating long-range chromatin interactions . Ak ı nc ı lar and colleagues ( 2 ) show that TERT reactivation by the proximal promoter mutation is directly mediated by a novel long-range chromatin interaction between the TERT promoter and a 300 kb upstream region (chr5: 1,556,087–1,558,758). GABPA proteins might generate long-range chromatin interactions by linking the mutant TERT promoter and the specifi c interacting region.