Dataset Information

NCoR controls glioblastoma tumor cell characteristics.

ABSTRACT:

Background

We have previously shown that the transcriptional coregulator NCoR represses astrocytic differentiation of neural stem cells, suggesting that NCoR could be a plausible target for differentiation therapy of glioblastoma.

Methods

To study a putative role for NCoR in regulating glioblastoma cell characteristics, we used RNA-mediated knockdown followed by analysis of gene expression, proliferation and cell growth, autophagy, invasiveness in vitro, and tumor formation in vitro and in vivo. We further performed chromatin immunoprecipitation of NCoR followed by genome-wide sequencing in the human glioblastoma cell line U87 in order to reveal NCoR-occupied loci.

Results

RNA knockdown of NCoR resulted in a moderate increase in differentiation accompanied by a significant decrease in proliferation in adherent U87 human glioblastoma cells. chromatin immunoprecipitation sequencing approach revealed alternative mechanisms underlying the decrease in proliferation, as NCoR was enriched at promoters of genes associated with autophagy such as ULK3. Indeed, signs of an autophagy response in adherent glioblastoma cells included an increased expression of autophagy genes, such as Beclin1, and increased lipidation and nuclear puncta of LC3. Intriguingly, in parallel to the effects in the adherent cells, NCoR knockdown resulted in a significant increase in anchorage-independent growth, and this glioblastoma cell population showed dramatic increases in invasive properties in vitro and tumor formation capacity in vitro and in vivo along with an increased proliferation rate.

Conclusion

Our results unveil unexpected aspects of NCoR regulation of tumor characteristics in glioblastoma cells and highlight the need for caution when transposing developmental concepts directly to cancer therapy.

SUBMITTER: Heldring N

PROVIDER: S-EPMC3895387 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Publications

NCoR controls glioblastoma tumor cell characteristics.

Heldring Nina N Nyman Ulrika U Lönnerberg Peter P Onnestam Sofie S Herland Anna A Holmberg Johan J Hermanson Ola O

Neuro-oncology 20131212 2

<h4>Background</h4>We have previously shown that the transcriptional coregulator NCoR represses astrocytic differentiation of neural stem cells, suggesting that NCoR could be a plausible target for differentiation therapy of glioblastoma.<h4>Methods</h4>To study a putative role for NCoR in regulating glioblastoma cell characteristics, we used RNA-mediated knockdown followed by analysis of gene expression, proliferation and cell growth, autophagy, invasiveness in vitro, and tumor formation in vit ...[more]

PMID: 24335696

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Project description:BackgroundGlioblastoma (GBM) is the most malignant, aggressive and recurrent primary brain tumor. Cell senescence can cause irreversible cessation of cell division in normally proliferating cells. According to studies, senescence is a primary anti-tumor mechanism that may be seen in a variety of tumor types. It halts the growth and spread of tumors. Tumor suppressive functions held by cellular senescence provide new directions and pathways to promote cancer therapy.MethodsWe comprehensively analyzed the cell senescence-associated genes expression patterns. The potential molecular subtypes were acquired based on unsupervised cluster analysis. The tumor immune microenvironment (TME) variations, immune cell infiltration, and stemness index between 3 subtypes were analyzed. To identify genes linked with GBM prognosis and build a risk score model, we used weighted gene co-expression network analysis (WGCNA), univariate Cox regression, Least absolute shrinkage and selection operator regression (LASSO), and multivariate Cox regression analysis. And the correlation between risk scores and clinical traits, TME, GBM subtypes, as well as immunotherapy responses were estimated. Immunohistochemistry (IHC) and cellular experiments were performed to evaluate the expression and function of representative genes. Then the 2 risk scoring models were constructed based on the same method of calculation whose samples were acquired from the CGGA dataset and TCGA datasets to verify the rationality and the reliability of the risk scoring model. Finally, we conducted a pan-cancer analysis of the risk score, assessed drug sensitivity based on risk scores, and analyzed the pathways of sensitive drug action.ResultsThe 3 potential molecular subtypes were acquired based on cell senescence-associated genes expression. The Log-rank test showed the difference in GBM patient survival between 3 potential molecular subtypes (P = 0.0027). Then, 11 cell senescence-associated genes were obtained to construct a risk-scoring model, which was systematically randomized to distinguish the train set (n = 293) and the test set (n = 292). The Kaplan-Meier (K-M) analyses indicated that the high-risk score in the train set (P < 0.0001), as well as the test set (P = 0.0053), corresponded with poorer survival. In addition, the high-risk score group showed a poor response to immunotherapy. The reliability and credibility of the risk scoring model were confirmed according to the CGGA dataset, TCGA datasets, and Pan-cancer analysis. According to drug sensitivity analysis, it was discovered that LJI308, a potent selective inhibitor of RSK pathways, has the highest drug sensitivity. Moreover, the GBM patients with higher risk scores may potentially be more beneficial from drugs that target cell cycle, mitosis, microtubule, DNA replication and apoptosis regulation signaling.ConclusionWe identified potential associations between clinical characteristics, TME, stemness, subtypes, and immunotherapy, and we clarified the therapeutic usefulness of cell senescence-associated genes.

Dataset Information

NCoR controls glioblastoma tumor cell characteristics.

Background

Methods

Results

Conclusion

Publications

NCoR controls glioblastoma tumor cell characteristics.

Similar Datasets

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