Tumor
cells forced to overexpress telomerase (left) are prone to increased growth and
colony formation. This can be reversed by reducing expression of NF-κB (right).
An
enzyme responsible for protecting chromosome ends stimulates tumorigenesis via
an unexpected mechanism
Chromosomes are capped by long, repetitive
DNA sequences called telomeres. These caps prevent genomic damage by insulating
against the steady shortening of DNA ends that naturally accompanies
replication. Once mature, cells generally stop producing the telomere-building
enzyme telomerase and stop dividing when these caps have shortened to a
critical length. However, many cancer cells get around this restriction by restoring
telomerase production, allowing uncontrolled growth.
Several studies have indicated that
telomerase performs functions other than chromosome capping.
Research from Vinay Tergaonkar’s team at the
A*STAR Institute of Molecular and Cell Biology in Singapore has revealed how
NF-κB — another protein abnormally activated in many cancers — not only
stimulates release of signals that promote an inflammatory response to help
beat back infectious threats, but can also establish physiological conditions that
favor cancerous growth if left unchecked1. “Chronic inflammation and telomerase
reactivation are hallmarks of most human cancers,” says Tergaonkar, “but the
mechanism of how enhanced NF-κB and telomerase activities are each sustained in
cancers is unknown.”
Their experiments revealed a surprisingly
close relationship between these processes. Boosting telomerase activity in
cultured human cancer cells enhanced tumorigenesis, but these effects could be
countered by forcing cells to produce lower levels of NF-κB. The researchers
subsequently demonstrated that telomerase directly enhances NF-κB activity (see
image), and found that genetically modified mice lacking telomerase showed a
greatly reduced inflammatory response following exposure to bacterial toxins.
Similar effects were apparent when
Tergaonkar’s team compared NF-κB activity in telomerase-producing and deficient
cells. Since both cell lines exhibited equivalent telomere lengths, these
results favor a telomere-independent mode of action. The researchers
demonstrated that telomerase binds directly to numerous NF-κB target genes, and
actually strengthens NF-κB’s association with several of these genomic sites.
For example, telomerase and NF-κB collaboratively stimulate production of the
major inflammatory signal interleukin-6 (IL-6). Tergaonkar and co-workers also
showed that a chemical inhibitor of telomerase dramatically reduced IL-6
production in a wide variety of leukemia cell lines.
Perhaps most importantly, the gene encoding
telomerase is itself a target of NF-κB, creating a ‘vicious circle’ of
signaling. “The two pathways fuel each other’s activities,” says Tergaonkar.
“These findings hence provide a unifying mechanism for the sustained
inflammation seen in a vast majority of cancers, and identify telomerase as a
novel regulator of inflammation.” In future efforts, his team will explore how
telomerase exerts its gene regulatory effects and seek out potential partner
molecules that assist in this process.
The A*STAR-affiliated researchers
contributing to this research are from the Institute of Molecular and Cell Biology
References
- Ghosh, A., Saginc, G., Leow, S. C., Khattar, E.,
Shin, E. M. et al. Telomerase directly regulates
NF-κB-dependent transcription. Nature Cell Biology 14, 1270–1281
(2012). | article
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