Journal
STEM CELLS
Volume 35, Issue 6, Pages 1468-1478Publisher
WILEY
DOI: 10.1002/stem.2621
Keywords
Genomic instability; Hypoxia; Cancer stem cells; Glioma; Ten-eleven-translocation (TET); Demethylation
Categories
Funding
- CSIR
- SERB-Young Investigator fellowship
- DBT
- SERB Women's Excellence-in-Research Grant
- DBT-Centre of Excellence grant
- R&D University grant
- Science and Engineering Research Board (SERB)
- Department of Biotechnology (DBT)
- UGC for SAP (BRS III)
- DST for FIST (level II) program
- DU-DST PURSE (phase II)
- Central Instrumentation Facility at UDSC
Ask authors/readers for more resources
Activation of pluripotency regulatory circuit is an important event in solid tumor progression and the hypoxic microenvironment is known to enhance the stemness feature of some cells. The distinct population of cancer stem cells (CSCs)/tumor initiating cells exist in a niche and augment invasion, metastasis, and drug resistance. Previously, studies have reported global hypomethylation and site-specific aberrant methylation in gliomas along with other epigenetic modifications as important contributors to genomic instability during glioma progression. Here, we have demonstrated the role of hypoxia-mediated epigenetic modifications in regulating expression of core pluripotency factors, OCT4 and NANOG, in glioma cells. We observe hypoxiamediated induction of demethylases, ten-eleven-translocation (TET) 1 and 3, but not TET2 in our cell-line model. Immunoprecipitation studies reveal active demethylation and direct binding of TET1 and 3 at the Oct4 and Nanog regulatory regions. Tet1 and 3 silencing assays further confirmed induction of the pluripotency pathway involving Oct4, Nanog, and Stat3, by these paralogues, although with varying degrees. Knockdown of Tet1 and Tet3 inhibited the formation of neurospheres in hypoxic conditions. We observed independent roles of TET1 and TET3 in differentially regulating pluripotency and differentiation associated genes in hypoxia. Overall, this study demonstrates an active demethylation in hypoxia by TET1 and 3 as a mechanism of Oct4 and Nanog overexpression thus contributing to the formation of CSCs in gliomas.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available