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Tet1 and 3: New Targets in the Battle against Invasive and Heterogeneous Brain Tumors?

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Review of “Hypoxia-Mediated Epigenetic Regulation of Stemness in Brain Tumor Cells” from STEM CELLS by Stuart P. Atkinson

The presence of hypoxia (low oxygen concentrations) and the development of cancer stem cells (CSCs) within solid tumors provide an environment that promotes cancer cell heterogeneity and, therefore, increases the complexity of treatment options. Studies suggest this is true of malignant glioblastomas (GBMs), brain tumors that suffer from high invasiveness, high heterogeneity, and poor prognosis [1].

Researchers from the laboratory of Tapasya Srivastava (University of Delhi, India) hoped to cut through this heterogeneity and discover targets for glioblastoma treatment by understanding how hypoxia epigenetically alters the expression of pluripotency genes associated with the formation of glioma CSCs [2]. 

Will their new STEM CELLS study help to develop novel targeted therapies for brain tumors and perhaps other hypoxia-and CSC-associated tumors [3]?

Initial experiments employing a GBM cell line (as a model for glioma) established that hypoxia increased self-renewal capability and induced pluripotency-associated gene expression, indicative of a shift towards a more undifferentiated phenotype. Hypoxic treatment also decreased the expression of several parts of the DNA methylation machinery and increased the expression of the ten-eleven-translocation (Tet) 1 and 3 proteins known to play a role in the active DNA demethylation. 

These changes manifested as a hypoxia-mediated increase of Tet1 and 3 binding at the regulatory regions of the Oct4 and Nanog pluripotency genes leading to a decrease in DNA methylation, the generation of a permissive chromatin environment, and an increase in gene expression (See figure for additional details). However, knockdown of Tet1 and Tet3 in GBM cells negated hypoxia-induced pluripotency gene expression and reduced GBM self-renewal capacity.

While this study highlights the complex mechanisms through which hypoxia promotes the formation of CSCs in gliomas, these findings also have relevance for the construction of treatment strategies for this highly heterogeneous cancer type. Targeting Tet1 and Tet2 with small molecule inhibitors to reduce stem cell characteristics may suppress CSC formation and allow us to bypass chemo- and radio-resistance.

Keep tuned to the Stem Cells Portal to discover all the most exciting new research on CSCs and the potential translation of these findings into treatment strategies!

Discussion Points

  • Can Tet1 and Tet3 inhibition in vivo inhibit tumor development?
  • Will this strategy work in other CSC-/hypoxia-related tumors?
  • Can small molecules that target histone modifying enzymes synergize with Tet1 and Tet3 inhibition?

References

  1. Olmez I, Shen W, McDonald H, et al. Dedifferentiation of patient-derived glioblastoma multiforme cell lines results in a cancer stem cell-like state with mitogen-independent growth. J Cell Mol Med 2015;19:1262-1272.
  2. Wong DJ, Liu H, Ridky TW, et al. Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell 2008;2:333-344.
  3. Prasad P, Mittal SA, Chongtham J, et al. Hypoxia-Mediated Epigenetic Regulation of Stemness in Brain Tumor Cells. STEM CELLS 2017;35:1468-1478.

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