Abstract
HDAC class IIa enzymes (HDAC4, 5, 7, 9) are important for glioma progression, invasion, responses to TMZ and radiotherapy, and prognosis. In this study, we demonstrated the efficacy of PET/CT/(MRI) with [18F]TFAHA for non-invasive and quantitative imaging of HDAC class IIa expression-activity in intracerebral 9L and U87-MG gliomas in rats. Increased accumulation of [18F]TFAHA in 9L and U87-MG tumors was observed at 20 min post radiotracer administration with SUV of 1.45 ± 0.05 and 1.08 ± 0.05, respectively, and tumor-to-cortex SUV ratios of 1.74 ± 0.07 and 1.44 ± 0.03, respectively. [18F]TFAHA accumulation was also observed in normal brain structures known to overexpress HDACs class IIa: hippocampus, n.accumbens, PAG, and cerebellum. These results were confirmed by immunohistochemical staining of brain tissue sections revealing the upregulation of HDACs 4, 5, and 9, and HIF-1α, hypoacetylation of H2AK5ac, H2BK5ac, H3K9ac, H4K8ac, and downregulation of KLF4. Significant reduction in [18F]TFAHA accumulation in 9L tumors was observed after administration of HDACs class IIa specific inhibitor MC1568, but not the SIRT1 specific inhibitor EX-527. Thus, PET/CT/(MRI) with [18F]TFAHA can facilitate studies to elucidate the roles of HDAC class IIa enzymes in gliomagenesis and progression and to optimize therapeutic doses of novel HDACs class IIa inhibitors in gliomas.
Highlights
Over the past two decades, several studies have demonstrated that GBM progression and recurrence is linked to epigenetic mechanisms including, mutations in IDH1/IDH2 genes, epigenetic modifying enzymes, histone deacetylases (HDACs), histone methyltransferases (HMTs), DNA methyltransferases (DNMT) and various DNA demethylases[1]
Non-invasive molecular imaging of expression-activity of HDAC class IIa enzymes may help in identification of GBM patients who may benefit from the addition of HDAC class IIa inhibitors to conventional TMZ-radiotherapy to improve the survival and overall outcome
We demonstrated that PET/CT/(MRI) with [18F]TFAHA allows a non-invasive, quantitive visualization of HDAC class IIa expression-activity in U87-MG and 9L intracerebral glioma models in rats
Summary
Over the past two decades, several studies have demonstrated that GBM progression and recurrence is linked to epigenetic mechanisms including, mutations in IDH1/IDH2 genes, epigenetic modifying enzymes, histone deacetylases (HDACs), histone methyltransferases (HMTs), DNA methyltransferases (DNMT) and various DNA demethylases[1]. Other studies reported opposite results; namely, that patients with methylated MGMT promoter and higher expression of HDAC4 had better survival after TMZ and radiation therapy[33,41] These observations suggest that HDACs class IIa and, in particular, the HDAC4 play key roles in determining responses to radiation-induced DNA damage and in maintaining cellular “stemness”, promoting radioresistance.
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