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Background Epigenetics may predict treatment sensitivity and clinical course for patients with meningiomas more accurately than histopathology. Nonetheless, targeting epigenetic mechanisms is understudied for pharmacotherapeutic development for these tumors. The bio-molecular insights and potential therapeutic development of meningioma epigenetics led us to investigate epigenetic inhibition in meningiomas. Methods We screened a 43-tumor cohort using a 139-compound epigenetic inhibitor library to assess sensitivity of relevant meningioma subgroups to epigenetic inhibition. The cohort was composed of 5 cell lines and 38 tumors cultured directly from surgery; mean patient age was 56.6 years ± 13.9 standard deviation. Tumor categories: 38 primary tumors, 5 recurrent; 33 from females, 10 from males; 32 = grade 1; 10 = grade 2; 1 = grade 3. Results Consistent with our previous results, histone deacetylase inhibitors (HDACi) were the most efficacious class. Panobinostat significantly reduced cell viability in 36 of 43 tumors; 41 tumors had significant sensitivity to some HDACi. G9a inhibition and Jumonji-domain inhibition also significantly reduced cell viability across the cohort; tumors that lost sensitivity to panobinostat maintained sensitivity to either G9a or Jumonji-domain inhibition. Sensitivity to G9a and HDAC inhibition increased with tumor grade; tumor responses did not separate by gender. Few differences were found between recurrent and primary tumors, or between those with prior radiation versus those without. Conclusions Few efforts have investigated the efficacy of targeting epigenetic mechanisms to treat meningiomas, making the clinical utility of epigenetic inhibition largely unknown. Our results suggest that epigenetic inhibition is a targetable area for meningioma pharmacotherapy. [ABSTRACT FROM AUTHOR]

Background Meningomas represent the most common primary intracranial tumor. Themajority are benignWorld Health Organization (WHO) Grade I lesions, but a subset of these behave in an aggressivemanner. Protein biomarkers are needed to distinguish aggressive from benign Grade I lesions. Materials and Methods Pooled protein lysates were derived from five clinically aggressive Grade I and five typically benign WHO Grade I tumors snap frozen at the time of surgery. Proteins were separated in each group using two-dimensional gel electrophoresis (2DGE) and protein spots of interest were identified using liquid chromatography-mass spectrometry (LC-MS). Potential biomarker candidates were validated using western blot assays in individual tumor samples and by tissue microarray (TMA). Results Seven candidate biomarkers were obtained from the 2DGE and validated via western blot and TMA. Biomarker validation data allowed for the creation of predictive models using binary logistical regression that correctly identified 85.9% of aggressive tumors within the larger cohort of Grade I meningioma. Conclusion Simple protein separation by 2DGE and identification of candidate biomarkers by LC-MS allowed for the identification of seven candidate biomarkers that when used in predictive models accurately distinguish aggressive from benign behavior in WHO Grade I meningioma. [ABSTRACT FROM AUTHOR]

Our group has previously reported that conditioned media derived from cardiac fibroblasts (Cfib) from the pulmonary hypertensive (PH)-right ventricle (RV) causes rapid and marked dedifferentiation of adult cardiac myocytes. However, the factor(s) responsible for dedifferentiation remain unidentified. Periostin, a 90kDa secreted protein, is nearly undetectable in the healthy adult heart, but is selectively re-expressed by fibroblasts following pressure overload. Periostin has been reported to stimulate cardiomyocyte cell cycle re-entry and regeneration, but its role in dedifferentiation is unknown, despite the observation that dedifferentiation is required for adult myocyte regeneration. We performed mass spectrometric analysis of the PH-RV Cfib secretome and identified that periostin is significantly upregulated compared to control (CO-RV). RNA-seq analysis also suggested higher expression of periostin in the PH-RV Cfib. qRT-PCR confirmed periostin to be upregulated nearly 8-fold compared to CO-RV. At the protein level, periostin expression was significantly upregulated in isolated PH-RV Cfib, but not in whole PH-RV homogenates, suggesting a Cfib-specific regulation and expression of periostin. In support of this hypothesis, immunohistochemical staining of the PH-RV demonstrated localization of periostin in the interstitial space, with little to no expression in the cardiomyocyte. Together, these data support the hypothesis that Cfib from the PH-RV synthesize and secrete periostin, contributing to myocyte dedifferentiation through a Cfib-cardiomyocyte axis. Ongoing experiments will test this hypothesis using biochemical, immunodepletion, and genetic approaches. [ABSTRACT FROM AUTHOR]

Histone deacetylase 5 (HDAC5) and HDAC9 are class IIa HDACs that function as signal-responsive repressors of the epigenetic program for pathological cardiomyocyte hypertrophy. The conserved deacetylase domains of HDAC5 and HDAC9 are not required for inhibition of cardiac hypertrophy. Thus, the biological function of class IIa HDAC catalytic activity in the heart remains unknown. Here we demonstrate that catalytic activity of HDAC5, but not HDAC9, suppresses mitochondrial reactive oxygen species generation and subsequent induction of NF-E2-related factor 2 (NRF2)-dependent antioxidant gene expression in cardiomyocytes. Treatment of cardiomyocytes with TMP195 or TMP269, which are selective class IIa HDAC inhibitors, or shRNA-mediated knockdown of HDAC5 but not HDAC9 leads to stimulation of NRF2-mediated transcription in a reactive oxygen species-dependent manner. Conversely, ectopic expression of catalytically active HDAC5 decreases cardiomyocyte oxidative stress and represses NRF2 activation. These findings establish a role of the catalytic domain of HDAC5 in the control of cardiomyocyte redox homeostasis and define TMP195 and TMP269 as a novel class of NRF2 activators that function by suppressing the enzymatic activity of an epigenetic regulator. [ABSTRACT FROM AUTHOR]