Novel mechanistic insights into cancer metastasis
22 Jul 2017
By Dr Shantanu Chowdhury, Senior Fellow
CSIR-IGIB, New Delhi
In the world of proteins, Telomerase achieved stardom in 2009 when discovery of functions of telomerase and telomeres in protecting human chromosomes received the Nobel Prize. Telomeres protect chromosome ends somewhat like the plastic clips at the end of shoelaces that prevent fraying of the ends, and telomerase makes telomeres. This is where telomerase is being good. However, less understood is how telomerase works like a 'criminal at night' - helping cancer cells to spread to other organs aggressively. In many cancers telomerase, somewhat mysteriously, becomes hyperactive. Whereas, in normal cells this is kept in check. We focused on the reasons behind why and how the check on telomerase production is lost. Mainly because we are trying to figure out how another protein called non-metastatic 2 (NME2) prevents cancer spread, also called metastasis.
Both, NME2 and telomerase find common ground in recent discoveries from our group. Presence of NME2, our results show, sharply reduces production of telomerase RNA (molecules that eventually give telomerase protein). Much like a security control check point, occupancy of NME2 at the telomerase promoter - a stretch of DNA sequence that takes critical decisions about when and how much telomerase RNA should be made - prevents production of telomerase RNA. On the other hand, low NME2 removes this check leading to high telomerase production.
Perhaps more interestingly, we find that NME2 engages a DNA structural form (instead of a stretch of DNA sequence, which is typically the case) at the telomerase promoter. We know this because we attempted to disrupt the structure and lost effects of NME2. But why is this important? Involvement of a DNA structural architecture allowed us to use molecules that recognize the specific structure - which in turn were able to function like NME2 by checking production of telomerase. Though several steps remain, this suggests something of importance in a clinical setting. In a large number or cancer patients hyperactive or reactivated telomerase was noted to result partly from mutations in the telomerase promoter. Importantly, these mutations occur in regions that are well placed for disrupting the security control check point(s) that hold telomerase production in check. Our recent work published in the Journal of Biological Chemistry suggests that small molecule agents may be useful in recovering the lost check points and bring telomerase production in control once again.
Epigenetic suppression of human telomerase (hTERT) is mediated by the metastasis suppressor NME2 in a G-quadruplex dependent fashion. Dhurjhoti Saha, Ankita Singh, Tabish Hussain, Vivek Srivastava, Suman Sengupta, Anirban Kar, Parashar Dhapola, Vishnu Dhople, Ramesh Ummani and Shantanu Chowdhury. Journal of Biological Chemistry. July 2017