Abstract 4673: EZH2 as a therapeutic target in glioblastoma: a cellular and molecular study

Abstract

Abstract Glioblastoma is the most common and deadliest malignant brain tumor in adults. It is currently treated with a combination of surgery, radiotherapy and chemotherapy with temozolomide (TMZ). Resistance to TMZ is a challenge in the treatment of this type of brain cancer. Epigenetic modulation is a new possibility to be tested against glioblastoma. Inhibition of EZH2, a histone methyltransferase (H3K27met3) which is overexpressed in cancer cells, leading to angiogenesis and metastasis, might be a new strategy to treat this tumor. In this work, the EZH2 inhibitor DZNeP was tested in A172 glioblastoma cells and in A172-TMZ-resistant glioblastoma cells. Inhibition of cell proliferation, cell adhesion, colony formation, and cell migration was noted in A172 and A172-TMZ-resistant glioblastoma cells after DZNeP treatment. DZNeP also 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: the expression of receptors involved in this pathway (TGFβR1 and TGFβR2) was decreased, and the expression of inhibitors of this pathway (BAMBI, SMAD6 and SMAD7) was increased. In order to support the results obtained by qRT-PCR about the TGFβ1 pathway, protein expression of SMAD2 and PSMAD2 was analyzed by Western blot. The ratio between PSMAD2/SMAD2 decreased in cells treated with DZNeP, which supports the possible therapeutic effect of this drug against the TGFβ pathway, as PSMAD2 is a negative prognostic marker in glioblastoma. In conclusion, we propose that inhibition of EZH2 might be considered as a therapeutic strategy against glioblastoma. Citation Format: Javier de la Rosa, Marta Iraburu, Gabriel Gallo-Oller, Alejandro Urdiciain, Xing Fan, Mehdi H. Shahi, Bárbara Meléndez, Juan A. Rey, Miguel A. Idoate, Javier S. Castresana. EZH2 as a therapeutic target in glioblastoma: a cellular and molecular study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4673. doi:10.1158/1538-7445.AM2017-4673