bims-malgli 2022-03-06 papers

Issue of 2022–03–06
six papers selected by
Oltea Sampetrean, Keio University

Neuro Oncol. 2022 Mar 01. pii: noac051. [Epub ahead of print]

RBBP4-p300 Axis Modulates Expression of Genes Essential for Cell Survival and is a Potential Target for Therapy in Glioblastoma.

Ann C Mladek, Huihuang Yan, Shulan Tian, Paul A Decker, Danielle M Burgenske, Katrina Bakken, Zeng Hu, Lihong He, Margaret A Connors, Brett L Carlson, Jonathan Wilson, Archana Bommi-Reddy, Andy Conery, Jeanette E Eckel-Passow, Jann N Sarkaria, Gaspar J Kitange.

BACKGROUND: RBBP4 activates transcription by histone acetylation, but the partner histone acetyltransferases are unknown. Thus, we investigated the hypothesis that RBBP4 interacts with p300 in a complex in glioblastoma (GBM).
METHODS: shRNA silencing of RBBP4 or p300 and RNAseq was used to identify genes co-regulated by RBBP4 and p300 in GBM43 patient derived xenograft (PDX). RBBP4/p300 complex was demonstrated using proximity ligation assay (PLA) and ChIPseq delineated histone H3 acetylation and RBBP4/p300 complex binding in promoters/enhancers. Temozolomide (TMZ)-induced DNA double strand breaks (DSBs) were evaluated by γ-H2AX and proliferation by CyQuant and live cell monitoring assays. In vivo efficacy was based on survival of mice with orthotopic tumors.
RESULTS: shRBBP4 and shp300 downregulated 4,768 genes among which 1,485 (31%) were commonly downregulated by both shRNAs, while upregulated genes were 2,484, including 863 (35%) common genes. The pro-survival genes were the top-ranked among the downregulated genes, including C-MYC. RBBP4/p300 complex was demonstrated in the nucleus, and shRBBP4 or shp300 significantly sensitized GBM cells to TMZ compared to the control shNT in vitro (p<0.05). Moreover, TMZ significantly prolonged the survival of mice bearing GBM22-shRBBP4 orthotopic tumors compared with control shNT tumors (median shNT survival 52 days vs. median shRBBP4 319 days; p=0.001). CREB-binding protein (CBP)/p300 inhibitor CPI-1612 suppressed H3K27Ac and RBBP4/p300 complex target proteins, including C-MYC, and synergistically sensitized TMZ in vitro. Pharmacodynamic evaluation confirmed brain penetration by CPI-1612 supporting further investigation to evaluate efficacy to sensitize TMZ.
CONCLUSIONS: RBBP4/p300 complex is present in GBM cells and is a potential therapeutic target.

Keywords: Glioblastoma; RBB4/p300 complex; histone-acetylation; temozolomide

DOI: https://doi.org/10.1093/neuonc/noac051

J Clin Invest. 2022 Mar 03. pii: e146536. [Epub ahead of print]

Up-regulated YB-1 protein promotes glioblastoma growth through an YB-1/CCT4/mLST8/mTOR pathway.

The Y-box binding protein 1 (YB-1) is a multi-functional RNA binding protein involved in virtually each step of RNA metabolism. However, the functions and mechanisms of YB-1 in one of the most aggressive cancers, glioblastoma, are not well understood. In this study, we identified that YB-1 protein was markedly overexpressed in glioblastoma and acted as a critical activator of both mTORC1 and mTORC2 signaling. Mechanistically, YB-1 bound the 5' untranslated region (UTR) of the CCT4 mRNA to promote the translation of CCT4, a component of CCT chaperone complex, that in turn activated the mTOR signal pathway by promoting mLST8 folding. In addition, YB-1 autoregulated its own translation by binding to its 5' UTR, leading to sustained activation of mTOR signaling. In glioblastoma patients, the protein level of YB-1 positively correlated with CCT4 and mLST8 expression as well as activated mTOR signaling. Importantly, the administration of RNA decoys specifically targeting YB-1 in a mouse xenograft model resulted in slower tumor growth and better survival. Taken together, these findings uncover a disrupted proteostasis pathway involving YB-1/CCT4/mLST8/mTOR axis in promoting glioblastoma growth, suggesting that YB-1 is a potential therapeutic target for the treatment of glioblastoma.

Keywords: Molecular biology; Oncology; Signal transduction; Translation

DOI: https://doi.org/10.1172/JCI146536

Brain Pathol. 2022 Mar 01. e13058

Enhanced expression of autophagy-related p62 without increased deposits of neurodegeneration-associated proteins in glioblastoma and surrounding tissue - An autopsy-based study.

Sigrid Klotz, Gerda Ricken, Matthias Preusser, Karin Dieckmann, Georg Widhalm, Karl Rössler, Peter Fischer, Ognian Kalev, Adelheid Wöhrer, Gabor G Kovacs, Ellen Gelpi.

Neurodegenerative diseases are a major health burden. The underlying causes are not yet fully understood, but different mechanisms such as cell stress and chronic inflammation have been described as contributing factors. Neurodegenerative changes have been observed in the vicinity of brain tumors, typically around slowly growing benign lesions. Moreover, in-vitro data suggest a potential induction of pathological tau deposits also in glioblastoma, a highly malignant and proliferative brain cancer. The aim of this study was to evaluate neurodegeneration-associated protein deposition and autophagy as well as microglial activation within and surrounding glioblastoma. Post-mortem brain tissue of 22 patients with glioblastoma was evaluated immunohistochemically for phosphorylated tau, beta-amyloid, alpha-synuclein and phosphorylated TDP-43. Additionally, the autophagy marker p62 and the microglial marker HLA-DR were investigated. The data was compared to 22 control cases and ten cases with other space occupying brain lesions. An increase of p62-immunoreactivity was observed within and adjacent to the glioblastoma tumor tissue. Moreover, dense microglial infiltration in the tumor tissue and the immediate surrounding brain tissue was a constant feature. Deposition of neurodegeneration-associated proteins was found in the majority of cases (86.4%) but in distant sites. These findings suggested a preexisting neurodegenerative pathology, which followed a typical distributional pattern: ten cases with Alzheimer disease neuropathological changes, including two severe cases, eight cases with primary age-related tauopathy, six cases with aging-related tau astrogliopathy and one case with progressive supranuclear palsy. Collectively, our data suggests enhanced autophagy in glioblastoma tumor cells and the surrounding brain. The variety and distribution of distant neurodegeneration-associated protein aggregates observed in the majority of cases, suggest a preexisting rather than a tumor-induced neurodegenerative condition.

Keywords: Tau; autophagy; glioblastoma; neurodegeneration; p62

DOI: https://doi.org/10.1111/bpa.13058

Neurotherapeutics. 2022 Feb 28.

RAGE Inhibitors as Alternatives to Dexamethasone for Managing Cerebral Edema Following Brain Tumor Surgery.

Shunan Liu, Yanyan Song, Ian Y Zhang, Leying Zhang, Hang Gao, Yanping Su, Yihang Yang, Shi Yin, Yawen Zheng, Lyuzhi Ren, Hongwei Holly Yin, Raju Pillai, Aritro Nath, Eric F Medina, Patrick A Cosgrove, Andrea H Bild, Behnam Badie.

Resection of brain tumors frequently causes injury to the surrounding brain tissue that exacerbates cerebral edema by activating an inflammatory cascade. Although corticosteroids are often utilized peri-operatively to alleviate the symptoms associated with brain edema, they increase operative morbidities and suppress the efficacy of immunotherapy. Thus, novel approaches to minimize cerebral edema caused by neurosurgical procedures will have significant utility in the management of patients with brain tumors. We have studied the role of the receptor for advanced glycation end products (RAGE) and its ligands on inflammatory responses to neurosurgical injury in mice and humans. Blood-brain barrier (BBB) integrity and neuroinflammation were characterized by Nanostring, flow cytometry, qPCR, and immunoblotting of WT and RAGE knockout mice brains subjected to surgical brain injury (SBI). Human tumor tissue and fluid collected from the resection cavity of patients undergoing craniotomy were also analyzed by single-cell RNA sequencing and ELISA. Genetic ablation of RAGE significantly abrogated neuroinflammation and BBB disruption in the murine SBI model. The inflammatory responses to SBI were associated with infiltration of S100A9-expressing myeloid-derived cells into the brain. Local release of pro-inflammatory S100A9 was confirmed in patients following tumor resection. RAGE and S100A9 inhibitors were as effective as dexamethasone in attenuating neuroinflammation. However, unlike dexamethasone and S100A9 inhibitor, RAGE inhibition did not diminish the efficacy of anti-PD-1 immunotherapy in glioma-bearing mice. These observations confirm the role of the RAGE axis in surgically induced neuroinflammation and provide an alternative therapeutic option to dexamethasone in managing post-operative cerebral edema.

Keywords: Glioblastoma; Human; Mice; Myeloid-derived cells; Neuroinflammation; S100A9

DOI: https://doi.org/10.1007/s13311-022-01207-w

Comput Math Methods Med. 2022 ;2022 9448144

Identification of Four Metabolic Subtypes of Glioma Based on Glycolysis-Cholesterol Synthesis Genes.

Jinsen Zhang, Xing Xiao, Qinglong Guo, Zixuan Wei, Wei Hua.

Based on alterations in gene expression associated with the production of glycolysis and cholesterol, this research classified glioma into prognostic metabolic subgroups. In this study, data from the CGGA325 and The Cancer Genome Atlas (TCGA) datasets were utilized to extract single nucleotide variants (SNVs), RNA-seq expression data, copy number variation data, short insertions and deletions (InDel) mutation data, and clinical follow-up information from glioma patients. Glioma metabolic subtypes were classified using the ConsensusClusterPlus algorithm. This study determined four metabolic subgroups (glycolytic, cholesterogenic, quiescent, and mixed). Cholesterogenic patients had a higher survival chance. Genome-wide investigation revealed that inappropriate amplification of MYC and TERT was associated with improper cholesterol anabolic metabolism. In glioma metabolic subtypes, the mRNA levels of mitochondrial pyruvate carriers 1 and 2 (MPC1/2) presented deletion and amplification, respectively. Differentially upregulated genes in the glycolysis group were related to pathways, including IL-17, HIF-1, and TNF signaling pathways and carbon metabolism. Downregulated genes in the glycolysis group were enriched in terpenoid backbone biosynthesis, nitrogen metabolism, butanoate metabolism, and fatty acid metabolism pathway. Cox analysis of univariate and multivariate survival showed that risks of glycolysis subtypes were significantly higher than other subtypes. Those results were validated in the CGGA325 dataset. The current findings greatly contribute to a comprehensive understanding of glioma and personalized treatment.

DOI: https://doi.org/10.1155/2022/9448144