Abstract
DNA repair promotes the progression and recurrence of glioblastoma (GBM). However, there remain no effective therapies for targeting the DNA damage response and repair (DDR) pathway in the clinical setting. Thus, we aimed to conduct a comprehensive analysis of DDR genes in GBM specimens to understand the molecular mechanisms underlying treatment resistance. Herein, transcriptomic analysis of 177 well-defined DDR genes was performed with normal and GBM specimens (n = 137) from The Cancer Genome Atlas and further integrated with the expression profiling of histone deacetylase 6 (HDAC6) inhibition in temozolomide (TMZ)-resistant GBM cells and patient-derived tumor cells. The effects of HDAC6 inhibition on DDR signaling were examined both in vitro and intracranial mouse models. We found that the expression of DDR genes, involved in repair pathways for DNA double-strand breaks, was upregulated in highly malignant primary and recurrent brain tumors, and their expression was related to abnormal clinical features. However, a potent HDAC6 inhibitor, MPT0B291, attenuated the expression of these genes, including RAD51 and CHEK1, and was more effective in blocking homologous recombination repair in GBM cells. Interestingly, it resulted in lower cytotoxicity in primary glial cells than other HDAC6 inhibitors. MPT0B291 reduced the growth of both TMZ-sensitive and TMZ-resistant tumor cells and prolonged survival in mouse models of GBM. We verified that HDAC6 regulated DDR genes by affecting Sp1 expression, which abolished MPT0B291-induced DNA damage. Our findings uncover a regulatory network among HDAC6, Sp1, and DDR genes for drug resistance and survival of GBM cells. Furthermore, MPT0B291 may serve as a potential lead compound for GBM therapy.
Highlights
Glioblastoma (GBM), the most common adult malignant brain tumor, is one of the deadliest cancers, as it involves a highly aggressive feature and causes poor prognosis even after simultaneous standard treatment with radiation and temozolomide (TMZ)-based chemotherapy [1, 2]
There is a lack of a systemic approach that integrates the genome-wide landscape of expression profiling, big data analytics, and clinical significance, which analysis of the overlapping genes using MetaCore software (Fig. 1D) identified that the top three process networks were “DSB repair”, “MMR repair”, and “BER-nucleotide excision repair (NER) repair”. These results suggest that histone deacetylase 6 (HDAC6) may be involved in regulating the abnormal might be critical issues in translational research for the application expression of the damage response and repair (DDR) genes affecting DNA repair
By further analysis of 177 well-defined DDR genes using hierarchical clustering, we identified 25 DDR genes that were significantly (p < 0.05) upregulated in primary and recurrent GBM (Fig. 1A)
Summary
Glioblastoma (GBM), the most common adult malignant brain tumor, is one of the deadliest cancers, as it involves a highly aggressive feature and causes poor prognosis even after simultaneous standard treatment with radiation and temozolomide (TMZ)-based chemotherapy [1, 2]. TMZ is an imidazotetrazine derivative of an alkylating agent and acts as a DNA methylating agent, thereby resulting in DNA lesion (O6-methylguanine, N7-methylguanine, and N3-methyladenine) and DNA mismatches to cause cellular senescence and apoptosis [3]. Promoter methylation of the DNA repair gene, O-6methylguanine-DNA methyltransferase (MGMT), which acts by removing alkyl groups from DNA, has been associated with longer survival in response to TMZ treatment [4]. Patients with isocitrate dehydrogenase (NADP(+)) 1 (IDH1)R132H mutation, a diagnostic marker and prognostic indicator of GBM, gain survival benefit in contrast to those without the mutation in both primary and secondary GBM [6, 7]. IDH1R132H mutation acquires neomorphic ability to produce D-2-hydroxyglutarate from αKG, causing cellular alterations resulting in metabolic dysfunction and inhibition of DNA repair [6]. Several studies shed light on the impact of IDH1R132H mutation with impaired DNA repair mechanisms, including inhibition of DNA repair enzyme alkB homolog 1, histone H2A dioxygenase
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