Dataset Information

Epigenetic-focused CRISPR-Cas9 screen identifies ASH2L as a regulator of Glioblastoma cell survival

ABSTRACT: Glioblastoma Multiforme (GBM) is the most common and aggressive primary brain tumor. Despite recent developments in surgery, chemo- and radiotherapy, a currently poor prognosis of GBM patients highlights an urgent need for novel treatment strategies. Our awareness on importance of epigenetic mechanisms for tumor initiation, progression and apoptotic response lead us to investigate epigenetic regulators of GBM survival through a genetic ablation screen. Screen with our custom library EPIDOKOL targeting functional domains of critical chromatin modifier genes, revealed multiple GBM essentiality gene candidates, most importantly ASH2L. Upon ASH2L ablation, we observed induction of apoptosis and cell cycle arrest concomitant with a set of downregulated signature genes. Massive reduction in tumor forming capacity of ASH2L depleted GBM cells as well as high ASH2L expression in GBM patients in comparison to low grade gliomas (LGG) proved essentiality of the gene for glioma cell fitness. Detection of epigenetic factors modulating tumor survival via high throughput, robust and affordable screens such as EPIDOKOL holds great promise to ultimately enable rapid discovery of novel cancer biomarkers and production of effective therapies which will increase life span and dignity of cancer patients.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

SUBMITTER: Tugba Bagci Onder

LAB HEAD: Tugba Bagci Onder

PROVIDER: PXD033358 | Pride | 2024-01-26

REPOSITORIES: Pride

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Epigenetic-focused CRISPR/Cas9 screen identifies (absent, small, or homeotic)2-like protein (ASH2L) as a regulator of glioblastoma cell survival.

Ozyerli-Goknar Ezgi E Kala Ezgi Yagmur EY Aksu Ali Cenk AC Bulut Ipek I Cingöz Ahmet A Nizamuddin Sheikh S Biniossek Martin M Seker-Polat Fidan F Morova Tunc T Aztekin Can C Kung Sonia H Y SHY Syed Hamzah H Tuncbag Nurcan N Gönen Mehmet M Philpott Martin M Cribbs Adam P AP Acilan Ceyda C Lack Nathan A NA Onder Tamer T TT Timmers H T Marc HTM Bagci-Onder Tugba T

Cell communication and signaling : CCS 20231116 1

<h4>Background</h4>Glioblastoma is the most common and aggressive primary brain tumor with extremely poor prognosis, highlighting an urgent need for developing novel treatment options. Identifying epigenetic vulnerabilities of cancer cells can provide excellent therapeutic intervention points for various types of cancers.<h4>Method</h4>In this study, we investigated epigenetic regulators of glioblastoma cell survival through CRISPR/Cas9 based genetic ablation screens using a customized sgRNA lib ...[more]

PMID: 37974198

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Project description:Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. The existence of a small population of stem-like tumor cells that efficiently propagate tumors and resist cytotoxic therapy is one proposed mechanism leading to the resilient behavior of tumor cells and poor prognosis. In this study, we performed an in-depth analysis of the DNA methylation landscape in GBM-derived cancer stem cells (GSCs). Parallel comparisons of primary tumors and GSC lines derived from these tumors with normal controls (a neural stem cell (NSC) line and normal brain tissue) identified groups of hyper- and hypomethylated genes that display a trend of either increasing or decreasing methylation levels in the order of controls, primary GBMs, and their counterpart GSC lines, respectively. Interestingly, concurrent promoter hypermethylation and gene body hypomethylation were observed in a subset of genes including MGMT, AJAP1 and PTPRN2. These unique DNA methylation signatures were also found in primary GBM-derived xenograft tumors indicating that they are not tissue culture-related epigenetic changes. Integration of GSC-specific epigenetic signatures with gene expression analysis further identified candidate tumor suppressor genes that are frequently down regulated in GBMs such as SPINT2, NEFM and PENK. Forced re-expression of SPINT2 reduced glioma cell proliferative capacity, anchorage independent growth, cell motility, and tumor sphere formation in vitro. The results from this study demonstrate that GSCs possess unique epigenetic signatures that may play important roles in the pathogenesis of GBM. The reduced representation bisulfite sequencing (RRBS) approach (Meissner et al., 2008) was used to generate genome-wide single-base resolution CpG methylation profiles of three primary GBMs (1063T, 1133T, and 1142T) and three GSC lines (1063S, 1133S, 1142S) derived from these primary GBM tumors. The NSC line and the normal brain (NB) tissue sample were used as controls for comparison purposes. In addition, we analyzed three GBM xenograft tumor tissue samples (Mayo22, Mayo39, Mayo59) developed by Dr. Jann N. Sarkaria of Mayo Clinic.

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