Dataset Information

NBM-BMX, an HDAC8 Inhibitor, Overcomes Temozolomide Resistance in Glioblastoma Multiforme by Downregulating the β-Catenin/c-Myc/SOX2 Pathway and Upregulating p53-Mediated MGMT Inhibition.

ABSTRACT: Although histone deacetylase 8 (HDAC8) plays a role in glioblastoma multiforme (GBM), whether its inhibition facilitates the treatment of temozolomide (TMZ)-resistant GBM (GBM-R) remains unclear. By assessing the gene expression profiles from short hairpin RNA of HDAC8 in the new version of Connectivity Map (CLUE) and cells treated by NBM-BMX (BMX)-, an HDAC8 inhibitor, data analysis reveals that the Wnt signaling pathway and apoptosis might be the underlying mechanisms in BMX-elicited treatment. This study evaluated the efficacy of cotreatment with BMX and TMZ in GBM-R cells. We observed that cotreatment with BMX and TMZ could overcome resistance in GBM-R cells and inhibit cell viability, markedly inhibit cell proliferation, and then induce cell cycle arrest and apoptosis. In addition, the expression level of β-catenin was reversed by proteasome inhibitor via the β-catenin/ GSK3β signaling pathway to reduce the expression level of c-Myc and cyclin D1 in GBM-R cells. BMX and TMZ cotreatment also upregulated WT-p53 mediated MGMT inhibition, thereby triggering the activation of caspase-3 and eventually leading to apoptosis in GBM-R cells. Moreover, BMX and TMZ attenuated the expression of CD133, CD44, and SOX2 in GBM-R cells. In conclusion, BMX overcomes TMZ resistance by enhancing TMZ-mediated cytotoxic effect by downregulating the β-catenin/c-Myc/SOX2 signaling pathway and upregulating WT-p53 mediated MGMT inhibition. These findings indicate a promising drug combination for precision personal treating of TMZ-resistant WT-p53 GBM cells.

SUBMITTER: Tsai CY

PROVIDER: S-EPMC8199487 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAccumulating evidence demonstrates the oncogenic roles of lncRNA (long non-coding RNA) molecules in a wide variety of cancer types including glioma. Equally important, However, tumorigenic functions of lncRNA in glioma remain largely unclear. A recent study suggested lncRNA SNHG15 played a role for regulating angiogenesis in glioma but its role in the tumor microenvironment (TME) was not investigated.MethodsFirst, we showed that SNHG15 was upregulated in GBM cells and associated with a poor prognosis for the patients of GBM using public databases. Next, we collected temozolomide sensitive (TMZ-S) and resistant (TMZ-R) clinical samples and demonstrated that co-culturing TMZ-R cells with HMC3 (microglial) cells promoted M2-polarization of HMC3 and the secretion of pro-GBM cytokines TGF-β and IL-6.ResultsComparative qPCR analysis of TMZ-S and TMZ-R cells showed that a significantly higher level of SNHG15, coincidental with a higher level of Sox2, β-catenin, EGFR, and CDK6 in TMZ-R cells. Subsequently, using bioinformatics tool, a potential mechanistic route for SNHG15 to promote GBM tumorigenesis was by inhibiting tumor suppressor, miR-627-5p which leads to activation of CDK6. Gene-silencing technique was employed to demonstrate that suppression of SNHG15 indeed led to the suppression of GBM tumorigenesis, accompanied by an increase miR-627-5p and decreased its two oncogenic targets, CDK6 and SOX-2. In addition, SNHG15-silenced TMZ-R cells became significantly sensitive towards TMZ treatment and less capable of promoting M2-phenotype in the HMC3 microglial cells. We then evaluated the potential anti-GBM activity of CDK6 inhibitor, palbociclib, using TMZ-R PDX mouse models. Palbociclib treatment significantly reduced tumorigenesis in TMZ-R/HMC3 bearing mice and SNHG15 and CDK6 expression was significantly reduced while miR-627-5p level was increased. Additionally, palbociclib treatment appeared to overcome TMZ resistance as well as reduced M2 markers in HMC3 cells.ConclusionTogether, we provided evidence supporting the usage of CDK6 inhibitor for TMZ-resistant GBM cases. Further investigation is warranted for the consideration of clinical trials.

Project description:BackgroundHeart failure is characterized by activation of the renin-angiotensin-aldosterone system, which is involved in the regulation of cardiac hypertrophy and hypertension. Recently, we reported that Hdac8 inhibition alleviates isoproterenol-induced and angiotensin II-induced cardiac hypertrophy or hypertension in mice. Here, the effect and regulatory mechanisms of the Hdac8 selective inhibitor PCI34051 on pressure overload-induced heart failure were examined.Methods and resultsAt week 6 posttransverse aortic constriction (TAC), mice were administered with PCI34051 (3, 10, or 30 mg/kg bodyweight/day) for 2 weeks. The therapeutic effects of PCI34051 on TAC-induced cardiac and lung hypertrophy were determined by examining the heart weight-to-bodyweight and lung weight-to-bodyweight ratios and the cross-sectional cardiomyocyte area. Echocardiography analysis revealed that PCI34051 mitigated TAC-induced decreased ejection fraction and fractional shortening. Additionally, the expression of Hdac8 was upregulated in the cardiac and pulmonary tissues of TAC mice. The expression levels of Ace1 and Agtr1 were upregulated, whereas those of Ace2 and Agtr2 were downregulated in TAC mice. PCI34051 treatment or Hdac8 knockdown alleviated inflammation as evidenced by Rela downregulation and Nfkbia upregulation in mice, as well as in cardiomyocytes, but not in cardiac fibroblasts. Hdac8 overexpression-induced Rela pathway activation was downregulated in Ace1 knockdown cells. Picrosirius red staining, real-time polymerase chain reaction, and western blotting analyses revealed that PCI34051 alleviated fibrosis and downregulated fibrosis-related genes. Moreover, PCI34051 or Hdac8 knockdown in rat cardiac fibroblasts alleviated cardiac fibrosis through the Tgfb1-Smad2/3 pathway. The results of overexpression and knockdown experiments revealed that Hdac8 and Ace1 promote inflammation and fibrosis.ConclusionsTreatment with PCI34051 enhanced cardiac and lung functions in the TAC-induced heart failure mouse model. These data suggest that HDAC8 is a potential novel therapeutic target for heart failure accompanied by pathological lung diseases.

Dataset Information

NBM-BMX, an HDAC8 Inhibitor, Overcomes Temozolomide Resistance in Glioblastoma Multiforme by Downregulating the β-Catenin/c-Myc/SOX2 Pathway and Upregulating p53-Mediated MGMT Inhibition.

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