Hypoxia-Mediated Epigenetic Regulation of Stemness in Brain Tumor Cells

Abstract

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 hypoxia-mediated 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. Stem Cells 2017;35:1468-1478.

Genome-wide analysis of the hypoxia-related DNA methylation-driven genes in lung adenocarcinoma progression

“…This phenomenon may be related to the down-regulation of DNA methyltransferases, and the regulation of histone modification and DNA methylation patterns [24,25]. The epigenetic regulation can further promote the hypoxic adaptive response, help tumor cells acquire more malignant phenotypes, and escape the toxic effects of radiotherapy and chemotherapy [26,27]. The prsent study explored the key genes involved in the development of hypoxia-associated LUAD, and their interactions with other factors.…”

Epigenetic induction of tumor stemness via the lipopolysaccharide-TET3-HOXB2 signaling axis in esophageal squamous cell carcinoma

“…In addition, the TET protein family has also been found to be involved in the regulation of CSCs. Prasad and colleagues demonstrated that hypoxic environment could induce the demethylation in glioma cells by overexpression of TET1 and TET3, then promoted the stemness of tumor cells by upregulating OCT4 and NANOG expression [42]. However, in ESCC, no study has reported the effect of the TET family on the stemness of tumor cells yet.…”

Epigenetic induction of tumor stemness via the Lipopolysaccharide-TET3-HOXB2 signaling axis in esophageal squamous cell carcinoma

“…Prasad and colleagues demonstrated that hypoxic environment could induce the demethylation in glioma cells by overexpression of TET1 and TET3, then promoted the stemness of tumor cells by upregulating OCT4 and NANOG expression [42]. However, in ESCC, no study has reported the effect of the TET family on the stemness of tumor cells yet.…”