NOVEL INVOLVEMENT OF TEN-ELEVEN-TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 1 (TET1) IN GLIAL CANCERS
Embargo until
2020-12-01
Date
2016-08-22
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Johns Hopkins University
Abstract
Malignant gliomas, including glioblastoma, are the most common form of brain tumors. Current median survival for glioblastoma with the standard of care in treatment is 14 to 15 months with 2-year survival hovering around 30% and 5-year survival close to 10%. Lower levels of TET1, a member of the Ten-Eleven-Translocation Methylcytosine Dioxygenase family, are detected in glioblastoma and associated with a decrease in median survival. The TET family mediates DNA demethylation. TET1 and TET2 are also tumor suppressors in hematopoietic malignancies. Moreover, TET1 is involved in the migration of different epithelial cell-derived cancers. Because TET1 has been shown to decrease survival in glioblastoma, I examined the involvement of TET1 in migration and the DNA damage response following treatment with ionizing radiation (IR) and topoisomerase inhibitors.
I used an in vitro approach that utilizes the stable knockdown of TET1 expression in human glioma cell lines. One pathway involved in DNA repair, non-homologous end joining (NHEJ), was impaired in TET1 deficient cells in response to DNA damage agents. Lower levels of H2AX and 53BP1 were observed, which was likely due to lower levels of DNA-PK. Interestingly, TET1 deficient cells displayed greater survival after being subjected to IR because of an impaired apoptotic response, which was likely due to lower levels of DNA-PK as well. Secondly, I found that the microenvironment influenced the migration of TET1 deficient cells. The migration of TET1 deficient cells was impaired on tissue culture plastic and fibronectin coated surfaces, but not on collagen coated surfaces. Collagen, however, recapitulates the surface of vascular structures tumor cells use to migrate along in the tumor. Therefore, TET1 deficient cells are likely less migratory in the tumor core and niches where collagen is low but display similar migration efficiency as TET1 expressing cells where collagen is present in the tumor. Taken together, the loss of TET1 greatly influences two important characteristics of gliomas that affect patient survival, resistance to therapy, and invasiveness.
My findings help further our current understanding of the interaction of glial cells differentially expressing TET1 in the tumor microenvironment. I suggest that drugs be targeted to DNA repair mechanisms that remain intact in TET1 deficient gliomas. Because NHEJ is attenuated in TET1 deficient gliomas, future studies should look at disruption of other DNA repair mechanisms such as homologous recombination to determine if pathway disruption would sensitize cells to radio- and chemotherapy treatments. Additionally, I also recommend targeting the migration pathways specific to TET1 regulation. Accordingly, it would be possible to reduce the migration of the low-TET1 expressing cell type that is more resistant to IR and other DNA damaging agents.
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Keywords
TET1, glioma