macroH2A2 antagonizes epigenetic programs of stemness in glioblastoma

Self-renewal is a crucial property of glioblastoma cells that is enabled by the choreographed functions of chromatin regulators and transcription factors. Identifying targetable epigenetic mechanisms of self-renewal could therefore represent an important step toward developing effective treatments for this universally lethal cancer. Here we uncover an epigenetic axis of self-renewal mediated by the histone variant macroH2A2. With omics and functional assays deploying patient-derived in vitro and in vivo models, we show that macroH2A2 shapes chromatin accessibility at enhancer elements to antagonize transcriptional programs of self-renewal. macroH2A2 also sensitizes cells to small molecule-mediated cell death via activation of a viral mimicry response. Consistent with these results, our analyses of clinical cohorts indicate that high transcriptional levels of this histone variant are associated with better prognosis of high-grade glioma patients. Our results reveal a targetable epigenetic mechanism of self-renewal controlled by macroH2A2 and suggest additional treatment approaches for glioblastoma patients

The neuroprotective role of somatostatin against beta amyloid induced toxicity in in vitro models of Alzheimer’s disease

Alzheimer’s disease (AD) is a chronic neurodegenerative disease affecting more than 60 million people worldwide. This debilitating disease harbors toxic environment to the brain causing neuronal cell death and causes general impairment of the cognitive function. In our laboratory, we have been studying the effect of somatostatin (SST) in serving neuroprotective role against various disease models including hyperinflammation, Huntington’s disease and AD. In the present study, we aim to study the mechanisms involved in SST mediated neuroprotection against beta amyloid induced toxicity in blood brain barrier and in neurons. In AD, the impaired clearance of β-amyloid peptide (Aβ) due to disrupted tight junction and transporter proteins is the prominent cause of disease progression. We demonstrate that SST prevents Aβ induced blood brain barrier permeability by regulating low density lipoprotein receptor-related protein and receptor for advanced glycation end products expression and improving the disrupted tight junction proteins. Furthermore, SST abrogates Aβ induced c-JUN NH2-terminal kinase phosphorylation and expression of matrix metalloproteinase. Next, as the neurites are often the initial point of damage upon accumulation of Aβ, we examined the role of SST in all-trans retinoic acid (RA) induced progression of neurite outgrowth in SH-SY5Y cells. We also determined the morphological changes in prominent intracellular markers of neurite growth including microtubule-associated protein 2, Tuj1 and Tau. Here, we present evidence that SST is a molecular determinant in regulating the transition of SH-SY5Y cells from non-neuronal entity to neuronal phenotype in response to RA. Lastly, to elucidate the mechanism involved in SST mediated protection against Aβ-induced toxicity in neurons, phosphorylation level of collapsing response mediator 2 (CRMP2), a well-established regulator of neurite homeostasis hyperphosphorylated in AD was monitored. We demonstrate that SST effectively inhibits the hyperphosphorylation of CRMP2 as Ser522, which plays a critical role in priming the phosphorylation of subsequent sites. Furthermore, we identified the underlying mechanism involved in the regulation of CRMP2 phosphorylation by monitoring the SST mediated regulation of calcium influx. Taken together, results presented here suggest that SST might serve as a therapeutic intervention in AD via targeting multiple pathways responsible for neurotoxicity, impaired BBB function and disease progression.Pharmaceutical Sciences, Faculty ofGraduat

Somatostatin Ameliorates β-Amyloid-Induced Cytotoxicity via the Regulation of CRMP2 Phosphorylation and Calcium Homeostasis in SH-SY5Y Cells

Somatostatin is involved in the regulation of multiple signaling pathways and affords neuroprotection in response to neurotoxins. In the present study, we investigated the role of Somatostatin-14 (SST) in cell viability and the regulation of phosphorylation of Collapsin Response Mediator Protein 2 (CRMP2) (Ser522) via the blockade of Ca2+ accumulation, along with the inhibition of cyclin-dependent kinase 5 (CDK5) and Calpain activation in differentiated SH-SY5Y cells. Cell Viability and Caspase 3/7 assays suggest that the presence of SST ameliorates mitochondrial stability and cell survival pathways while augmenting pro-apoptotic pathways activated by Aβ. SST inhibits the phosphorylation of CRMP2 at Ser522 site, which is primarily activated by CDK5. Furthermore, SST effectively regulates Ca2+ influx in the presence of Aβ, directly affecting the activity of calpain in differentiated SH-SY5Y cells. We also demonstrated that SSTR2 mediates the protective effects of SST. In conclusion, our results highlight the regulatory role of SST in intracellular Ca2+ homeostasis. The neuroprotective role of SST via axonal regeneration and synaptic integrity is corroborated by regulating changes in CRMP2; however, SST-mediated changes in the blockade of Ca2+ influx, calpain expression, and toxicity did not correlate with CDK5 expression and p35/25 accumulation. To summarize, our findings suggest two independent mechanisms by which SST mediates neuroprotection and confirms the therapeutic implications of SST in AD as well as in other neurodegenerative diseases where the effective regulation of calcium homeostasis is required for a better prognosis

Dysregulation of chromatin organization in pediatric and adult brain tumors: oncoepigenomic contributions to tumorigenesis and cancer stem cell properties

The three-dimensional (3D) organization of the genome is a crucial enabler of cell fate, identity, and function. In this review, we will focus on the emerging role of altered 3D genome organization in the etiology of disease, with a special emphasis on brain cancers. We discuss how different genetic alterations can converge to disrupt the epigenome in childhood and adult brain tumors, by causing aberrant DNA methylation and by affecting the amounts and genomic distribution of histone post-translational modifications. We also highlight examples that illustrate how epigenomic alterations have the potential to affect 3D genome architecture in brain tumors. Finally, we will propose the concept of “epigenomic erosion” to explain the transition from stem-like cells to differentiated cells in hierarchically organized brain cancers.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Somatostatin Ameliorates β-Amyloid-Induced Cytotoxicity via the Regulation of CRMP2 Phosphorylation and Calcium Homeostasis in SH-SY5Y Cells

Somatostatin is involved in the regulation of multiple signaling pathways and affords neuroprotection in response to neurotoxins. In the present study, we investigated the role of Somatostatin-14 (SST) in cell viability and the regulation of phosphorylation of Collapsin Response Mediator Protein 2 (CRMP2) (Ser522) via the blockade of Ca²⁺ accumulation, along with the inhibition of cyclin-dependent kinase 5 (CDK5) and Calpain activation in differentiated SH-SY5Y cells. Cell Viability and Caspase 3/7 assays suggest that the presence of SST ameliorates mitochondrial stability and cell survival pathways while augmenting pro-apoptotic pathways activated by Aβ. SST inhibits the phosphorylation of CRMP2 at Ser522 site, which is primarily activated by CDK5. Furthermore, SST effectively regulates Ca²⁺ influx in the presence of Aβ, directly affecting the activity of calpain in differentiated SH-SY5Y cells. We also demonstrated that SSTR2 mediates the protective effects of SST. In conclusion, our results highlight the regulatory role of SST in intracellular Ca²⁺ homeostasis. The neuroprotective role of SST via axonal regeneration and synaptic integrity is corroborated by regulating changes in CRMP2; however, SST-mediated changes in the blockade of Ca²⁺ influx, calpain expression, and toxicity did not correlate with CDK5 expression and p35/25 accumulation. To summarize, our findings suggest two independent mechanisms by which SST mediates neuroprotection and confirms the therapeutic implications of SST in AD as well as in other neurodegenerative diseases where the effective regulation of calcium homeostasis is required for a better prognosis.Pharmaceutical Sciences, Faculty ofReviewedFacult