Abstract
Glioblastoma is the most common malignant brain tumor in adults and it is currently treated with a combination of surgery, radiotherapy and chemotherapy with temozolomide (TMZ). Many patients show resistance to TMZ, which is a challenge in the treatment of this type of brain cancer. New strategies are being tested, like the inhibition of EZH2, a histone methyltransferase which is overexpressed in cancer cells, leading to angiogenesis and metastasis. In this work, the EZH2 inhibitor DZNeP was tested in A172 glioblastoma cells and in A172-TMZ-resistant glioblastoma cells. Inhibition of cell proliferation, adhesion, colony formation, and migration was noted in control and TMZresistant glioblastoma cells after DZNeP treatment. At the level of EZH2 target gene expression, DZNeP decreased EZH2 expression, and increased the expression of its target genes (E-cadherin and TIMP3), which might probably contribute to inhibiting the development of a cancer metastatic phenotype. Finally, DZNeP negatively regulated the TGFβ pathway. In conclusion, we propose that inhibition of EZH2 might be considered as a therapeutic strategy against glioblastoma.
Highlights
Glioblastoma [1,2] is the most common form of malignant brain cancer in adults, and it represents 12-15% of all intracranial tumors, and 50-60% of astrocytic tumors
Cell adhesion assay The goal of this assay was to test the adhesion capacity of A172 glioblastoma cells at 4 different conditions: control A172, control A172 treated with DZNeP, A172-TMZ-resistant, and A172-TMZ-resistant treated with DZNeP
Genes related to transforming growth factor β1 (TGFβ1) (SMAD6, SMAD7, TGFβR1, TGFβR2, TGFβ2, TGFβ3, BAMBI) pathway were analyzed in control A172, and in control A172 treated with DZNeP
Summary
Glioblastoma [1,2] is the most common form of malignant brain cancer in adults, and it represents 12-15% of all intracranial tumors, and 50-60% of astrocytic tumors. Very uncommon, it is highly lethal with the worst prognosis of any brain tumor and a 5-year survival rate of only 5% [1]. Addition of temozolomide (TMZ) to radiotherapy has resulted in an overall increase in survival of glioblastoma patients, therapy still fails in most cases, due to incomplete tumor resection, and/or to the apparent resistance of tumor cells to irradiation and TMZ. TMZ resistance and radiotherapy resistance represent a major challenge in the treatment of this disease [3,4,5]
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