TY - JOUR
T1 - Epigenetic suppression of human telomerase (hTERT) is mediated by the metastasis suppressor NME2 in a G-quadruplex– dependent fashion
AU - Saha, Dhurjhoti
AU - Singh, Ankita
AU - Hussain, Tabish
AU - Srivastava, Vivek
AU - Sengupta, Suman
AU - Kar, Anirban
AU - Dhapola, Parashar
AU - Dhople, Vishnu
AU - Ummanni, Ramesh
AU - Chowdhury, Shantanu
N1 - Funding Information:
This work was supported by Wellcome Trust/Department of Biotechnology (DBT) India Alliance Grant 500127/Z/09/Z (to S. C.) and fellowships from the Wellcome Trust/DBT India Alliance (to D. S., S. S., V. S., and A. K.), Indian Council of Medical Research (to A. S.), and Council of Scientific and Indus-trial Research (to T. H.). The authors declare that they have no conflicts of interest with the contents of this article. Author’s Choice—Final version free via Creative Commons CC-BY license. This article contains supplemental Figs. S1–S5 and Tables S1 and S2. 1 Both authors made equal contributions to this work. 2Present address: National Institute of Cancer Prevention and Research, Noida, Uttarpradesh 201301, India. 3Present address: Dept. of Biochemistry, School of Basic Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh 201306, India. 4Present address: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295. 5Present address: Dept. of Functional Genomics, University of Greifswald, Domstrasse 11, 17489 Greifswald, Germany. 6To whom correspondence should be addressed. E-mail: shantanuc@ igib.res.in.
Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2017/9/15
Y1 - 2017/9/15
N2 - Transcriptional activation of the human telomerase reverse transcriptase (hTERT) gene, which remains repressed in adult somatic cells, is critical during tumorigenesis. Several transcription factors and the epigenetic state of the hTERT promoter are known to be important for tight control of hTERT in normal tissues, but the molecular mechanisms leading to hTERT reactivation in cancer are not well-understood. Surprisingly, here we found occupancy of the metastasis suppressor non-metastatic 2 (NME2) within the hTERT core promoter in HT1080 fibrosarcoma cells and HCT116 colon cancer cells and NME2-mediated transcriptional repression of hTERT in these cells. We also report that loss of NME2 results in up-regulated hTERT expression. Mechanistically, additional results indicated that the RE1-silencing transcription factor (REST)–lysine-specific histone demethylase 1 (LSD1) co-repressor complex associates with the hTERT promoter in an NME2-dependent way and that this assembly is required for maintaining repressive chromatin at the hTERT promoter. Interestingly, a G-quadruplex motif at the hTERT promoter was essential for occupancy of NME2 and the REST repressor complex on the hTERT promoter. In light of this mechanistic insight, we studied the effects of G-quadruplex– binding ligands on hTERT expression and observed that several of these ligands repressed hTERT expression. Together, our results support a mechanism of hTERT epigenetic control involving a G-quadruplex promoter motif, which potentially can be targeted by tailored small molecules.
AB - Transcriptional activation of the human telomerase reverse transcriptase (hTERT) gene, which remains repressed in adult somatic cells, is critical during tumorigenesis. Several transcription factors and the epigenetic state of the hTERT promoter are known to be important for tight control of hTERT in normal tissues, but the molecular mechanisms leading to hTERT reactivation in cancer are not well-understood. Surprisingly, here we found occupancy of the metastasis suppressor non-metastatic 2 (NME2) within the hTERT core promoter in HT1080 fibrosarcoma cells and HCT116 colon cancer cells and NME2-mediated transcriptional repression of hTERT in these cells. We also report that loss of NME2 results in up-regulated hTERT expression. Mechanistically, additional results indicated that the RE1-silencing transcription factor (REST)–lysine-specific histone demethylase 1 (LSD1) co-repressor complex associates with the hTERT promoter in an NME2-dependent way and that this assembly is required for maintaining repressive chromatin at the hTERT promoter. Interestingly, a G-quadruplex motif at the hTERT promoter was essential for occupancy of NME2 and the REST repressor complex on the hTERT promoter. In light of this mechanistic insight, we studied the effects of G-quadruplex– binding ligands on hTERT expression and observed that several of these ligands repressed hTERT expression. Together, our results support a mechanism of hTERT epigenetic control involving a G-quadruplex promoter motif, which potentially can be targeted by tailored small molecules.
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U2 - 10.1074/jbc.M117.792077
DO - 10.1074/jbc.M117.792077
M3 - Article
C2 - 28717007
AN - SCOPUS:85029579743
SN - 0021-9258
VL - 292
SP - 15205
EP - 15215
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 37
ER -