Histone deacetylase 6 acts upstream of DNA damage response activation to support the survival of glioblastoma cells

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.

Adapt to Persist: Glioblastoma Microenvironment and Epigenetic Regulation on Cell Plasticity

“…HDACs not only remove acetyl groups from histones but also interact with transcription factors, acting as co-repressors or co-activators of gene expression [ 145 ]. HDACs have been widely studied in GBM cells due to their relationship with therapeutic resistance, cell proliferation and invasion, angiogenesis and apoptosis [ 146 , 147 , 148 , 149 ]. In fact, a wide variety of HDAC inhibitors (HDACi) have been tested in clinical trials for the treatment of different types of cancer, including GBM [ 150 , 151 ].…”

“…HDACs have been shown to downregulate TERT transcript levels, while increasing its protein stability [ 156 ]. The HDAC1/2/6/Sp1 pathway upregulates TERT, and treatment with azaindolyl sulfonamide (MPT0B291), an inhibitor of HDAC6 with partial effect on HDAC1/2, induces G2/M arrest and senescence in GSCs [ 157 ], as well as decreased growth in both TMZ-sensitive and -resistant cells [ 149 ]. Data suggest that TA is increased in GSCs relative to differentiated glioma cells.…”

Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance

“…HDAC6 was shown to promote the invasion and migration of rhabdomyosarcoma (RMS) cells via RAC1, a Rho family GTPase [ 22 ]. HDAC6 also promoted the proliferation of glioblastoma by increasing the levels of DNA damage response genes such as DNA repair protein 51 (RAD51) and checkpoint kinase 1 (CHEK1) [ 23 ].…”

“…TMPRSS4 promoted tumor cell proliferation and metastasis by inducing specificity protein 1/3 (Sp1/3), activator protein-1 (AP-1), and NF-κB transcription factors [ 31 ]. Sp1 is a novel substrate of HDAC6 [ 23 ].…”

Multifaceted Influence of Histone Deacetylases on DNA Damage Repair: Implications for Hepatocellular Carcinoma

“…60 In contrast, HDAC6 activates its downstream factor, Sp1, to upregulate RAD51, CHEK1, EXO1, RAD54L, and GEN1, promoting HR repair in glioblastoma cells. 61 As an epistatic gene of BRCA1, HDAC10 can compensate for the loss of BRCA1 in the cell repair process and reduce the appearance of DSBs. Although BRCA1 is lost, ovarian carcinoma cells can still exert their repair function by HDAC10, while loss of HDAC10 worsens the DSB repair defect.…”