The possible prognostic role of histone deacetylase and transforming growth factor β/Smad signaling in high grade gliomas treated by radio-chemotherapy: a preliminary immunohistochemical study

Abstract

Glioblastoma (GBM) is the most common and aggressive tumor of the central nervous system. Unfortunately, patients affected by this disease have a very poor prognosis, due to high level of invasiveness and resistance to standard therapies. Although the molecular profile of GBM has been extensively investigated, the events responsible for its pathogenesis and progression remain largely unknown. Histone Deacetylases (HDAC) dependent epigenetic modifications and transforming growth factor (TGF)-β/Smad pathway seem to play an important role in GBM tumorigenesis, resistance to common therapies and poor clinical outcome. The aim of this study was to evaluate the involvement and the possible interaction between these two molecular cascades in the pathogenesis and prognosis of GBM. Immunohistochemistry (IHC) was performed on microdissected GBM samples, collected from 14 patients (6 men and 8 women) ranging in age from 43 to 74 years. The patients were previously divided, on the basis of their overall survival (OS), into two groups: short and long OS. Patients with poor prognosis showed hyperexpression of HDAC4 and HDAC6, an activation of the TGF-β/Smad pathway, with high levels of IL-13, SMAD2, PDGF and MMP3 expression, compared to the long survivors. The short OS group exhibits a decrease in SMAD7 expression and also low levels of p21 immunostaining, which represents a common target of the two pathways. The IHC data was confirmed by quantitative analysis and Immunoblotting. Our preliminary results suggest that both HDAC4 and HDAC6 together with the TGF-β/Smad pathway may be involved in progression of GBM and this cross talking could be a useful prognostic marker in this deadly disease.

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

“…16,23 Highly expressed HDAC4 is positively correlated with the tumor grade and negatively correlated with overall survival rates. 40,41 Recently, HDAC4-mediated transcriptional suppression of p21 expression has been found to contribute to malignant proliferation of gliomas, 23 as well as other cancer cells, including breast cancer, 42 colon cancer 43 and lung adenocarcinoma, 44 implying that HDAC4 nuclear import is most likely predominant due to its role in tumorigenesis. Through IHC analysis, we found that the rates of nuclear HDAC4 significantly increased among Grade II, III and Grade IV glioma samples and were positively correlated with the grades.…”

“…In glioma cells, HDAC4 activity has been implicated in invasion, proliferation, and drug and radiation resistance . Highly expressed HDAC4 is positively correlated with the tumor grade and negatively correlated with overall survival rates . Recently, HDAC4‐mediated transcriptional suppression of p21 expression has been found to contribute to malignant proliferation of gliomas, as well as other cancer cells, including breast cancer, colon cancer and lung adenocarcinoma, implying that HDAC4 nuclear import is most likely predominant due to its role in tumorigenesis.…”

Implication for Cancer Stem Cells in Solid Cancer Chemo-Resistance: Promising Therapeutic Strategies Based on the Use of HDAC Inhibitors

“…In breast cancer, the involvement of HDAC6 in the Hippo pathway-regulating network was demonstrated by downregulation of YAP protein levels [53] and by a strong acetylation and destabilization of the tumor suppressor MST1 [54]. Some evidence suggests that HDAC6 plays a role in theTGFβ−SMAD activation pathway, and thus its inhibition establishes a decrease in EMT induction [55,56]. Finally, most recently, it has been shown that HDAC6 inhibition leads to inactivation of Gli1, resulting in glioma cancer cell radio-sensitization [57].…”

Molecular imaging HDACs class IIa expression-activity and pharmacologic inhibition in intracerebral glioma models in rats using PET/CT/(MRI) with [18F]TFAHA

“…Previous studies in non-CNS tumors, aimed to identify targets for radiosensitization using siRNA and shRNA-mediated knockdown of individual HDAC isoforms, revealed HDACs class IIa as potential targets for pharmacologic inhibition 12,34–38 . Recently, it was demonstrated that that the level of HDAC4 expression of GBMs negatively correlates with overall survival rates after temozolomide and radiation therapy 39,40 . Moreover, high HDAC4 expression was found to be a strong predictive factor of poor outcome of TMZ treatment of GBM, independent of MGMT status and Ki67 index.…”