Silencing of Histone Deacetylase 6 Decreases Cellular Malignancy and Contributes to Primary Cilium Restoration, Epithelial-to-Mesenchymal Transition Reversion, and Autophagy Inhibition in Glioblastoma Cell Lines

Abstract

Glioblastoma multiforme, the most common type of malignant brain tumor as well as the most aggressive one, lacks an effective therapy. Glioblastoma presents overexpression of mesenchymal markers Snail, Slug, and N-Cadherin and of the autophagic marker p62. Glioblastoma cell lines also present increased autophagy, overexpression of mesenchymal markers, Shh pathway activation, and lack of primary cilia. In this study, we aimed to evaluate the role of HDAC6 in the pathogenesis of glioblastoma, as HDAC6 is the most overexpressed of all HDACs isoforms in this tumor. We treated glioblastoma cell lines with siHDAC6. HDAC6 silencing inhibited proliferation, migration, and clonogenicity of glioblastoma cell lines. They also reversed the mesenchymal phenotype, decreased autophagy, inhibited Shh pathway, and recovered the expression of primary cilia in glioblastoma cell lines. These results demonstrate that HDAC6 might be a good target for glioblastoma treatment.

The Tubulin Code and Tubulin-Modifying Enzymes in Autophagy and Cancer

“…In line with these studies, aberrant expression of tubulin deacetylase HDAC6 has been reported in several cancer cell lines and tumor models [70,71]. In addition, upregulation of HDAC6 increases cell motility in breast cancer cells, thus contributing to cancer metastasis [72], whereas in glioblastoma cells genetic silencing of HDAC6 decreases cellular malignancy and reverses the mesenchymal phenotype [73,74]. High level Lung Treatment response to paclitaxel [64] On the other hand, the role of tubulin deacetylase SIRT2 in cancer is controversial, as SIRT2 exerts either tumor-suppressive or oncogenic properties.…”

“…In line with these studies, aberrant expression of tubulin deacetylase HDAC6 has been reported in several cancer cell lines and tumor models [ 70 , 71 ]. In addition, upregulation of HDAC6 increases cell motility in breast cancer cells, thus contributing to cancer metastasis [ 72 ], whereas in glioblastoma cells genetic silencing of HDAC6 decreases cellular malignancy and reverses the mesenchymal phenotype [ 73 , 74 ].…”

The Emerging Role of EVA1A in Different Types of Cancers

“…Therefore, there is an urgent need to explore the pathogenesis of this disease and find an effective treatment. Autophagy has been reported to play an important role in GBM; however, the mechanism is not completely clear [ 63 , 64 , 65 ]. Xue Shen and colleagues transfected the recombinant adenovirus 5-EVA1A vector (ad5-EVA1A) into glioblastoma (GBM) cells to overexpress EVA1A in order to analyse its antitumor activity in vitro.…”

Hedgehog signaling regulates the development and treatment of glioblastoma (Review)

“…The three mixed phosphorylated polypeptides derived from GLI2 significantly increased the level of GLI2 phosphorylation and decreased the transcriptional activation of GLI2, and the radiation sensitization of GBM cells was significantly higher than that in the control group ( 128 ). HDAC6 was upregulated in GSCs and inhibited HDAC6 down-regulated glioma-associated oncogene GLI1 and PTCH1/2 receptors, as well as SHH signaling components, expression and activity, thereby inhibiting GSC proliferation, inducing differentiation and increasing the apoptosis rate through the SHH/GLI1 signaling pathway ( 109 , 129 ). Inhibition of HDAC6 by Tubasatin A enhanced the radiosensitivity of GBM tumor cells.…”