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A HOTAIR regulatory element modulates glioma cell sensitivity to temozolomide through long-range regulation of multiple target genes

ABSTRACT: Temozolomide (TMZ) is a frequently used chemotherapy for glioma; however, chemoresistance is a major problem limiting its effectiveness. Thus knowledge of mechanisms underlying this outcome could improve patient prognosis. Here, we report that deletion of a regulatory element in the HOTAIR locus increases glioma cell sensitivity to TMZ and alters transcription of multiple genes. Analysis of a combination of RNA-seq, Capture HiC and patient survival data suggests that CALCOCO1 and ZC3H10 are target genes repressed by the HOTAIR regulatory element and that both function in regulating glioma cell sensitivity to TMZ. Rescue experiments and TAD analysis based on HiC data confirmed this hypothesis. We propose a new regulatory mechanism governing glioma cell TMZ sensitivity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE125629 | GEO | 2019/01/25

REPOSITORIES: GEO

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MGMT enhancer modulates glioma cell sensitivity to temozolomide through long-range regulations of multiple genes

Project description:Acquired resistance of temozolomide (TMZ) is one of the major obstacle of glioblastoma clinical treatment and the mechanism of TMZ resistance is still not very clear. In the presented research we show that deletion of rs16906252-associated MGMT enhancer in MGMT negative glioma cells induced increase sensitivity to temozolomide and combination of RNA-seq and Capture HiC identified several long-range target genes of rs16906252-associated MGMT enhancer. In addition, HiC data shows alterations of chromatin structures in glioma cells survived from high-dosage TMZ treatment and changes of TADs influence rs16906252-associated MGMT enhancer’s long-range regulations of target genes. Our study suggests rs16906252-associated MGMT enhancer regulates glioma cells’ TMZ sensitivity by long-range regulations of several target genes, which is a novel mechanism of regulation of TMZ sensitivity in glioma cells.

2020-04-02 | GSE129476 | GEO

Bivalent activity of super-enhancer RNA LINC02454 controls 3D chromatin structure and regulates glioma sensitivity to temozolomide.

Project description:Temozolomide (TMZ) resistance of glioma cells is currently a critical problem in glioma clinical treatment. In this study, we reveal a bivalent function of a super-enhancer RNA LINC02454 in modulating glioma cell sensitivity to TMZ via regulation of SORBS2 and DDR expression. LINC02454 increased TMZ sensitivity by maintaining 3D chromatin structure and promoting SORBS2 expression, but paradoxically decreased TMZ sensitivity by binding to the DDR1 locus and promoting DDR1 transcription. This study proposes a new regulatory mechanism governing glioma cell sensitivity to TMZ and provides new insights that may improve therapies against glioma.

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HOTAIR knockdown glioma cell proteomics

Project description:This study demonstrated the effects of lncRNA HOTAIR knockdown on the glioma proteomics. An abnormally high expression of the lncRNA HOTAIR has been previously demonstrated in glioma cells. HOTAIR regulates genes by anchoring epigenetic modification proteins and causes abnormalities in multiple signaling pathways. We knocked down HOTAIR in glioma cells by siRNA with SILAC labeling, and then total protein was extracted for proteome mass spectrometry.

2021-12-31 | PXD029919 | iProX

A Novel Glioma-specific Enhancer Maintains Glioma Temozolomide Sensitivity By Regulation of RasGRP3 Expression via Long-range Chromosome Interactions

Project description:In this study, we report the identification of a glioma-specific enhancer that confers sensitivity to TMZ by upregulation of the mitogen-associated protein kinase activator RasGRP3. Deletion of either the active domain of RasGPR3 or the enhancer using CRISPR/Cas9, was sufficient to restore sensitivity to TMZ in a resistant population of cells that was reversed with overexpression of RasGRP3. The project include RNA-seq, Hi-C, Capture Hi-C between DMSO-treated U251 and TMZ-treated U251.

2019-01-18 | GSE125243 | GEO

16s rDNA-sequencing of gut microbiota in Temozolomide-treated glioma mice

Project description:Purpose: Gut microbiota is associated with the progression of brain tumor. However, the alterations in the gut microbiota during glioma growth and temozolomide (TMZ) therapy remains to be understood. Methods: C57BL/6 male mice were implanted with GL261 glioma cells. TMZ/sodium carboxymethyl cellulose (SCC) was administered by gavage for five consecutive days (from 8 to 12 days after implantation). Fecal samples were collected before (T0) and on days 7 (T1), 14 (T2), and 28 (T3) after implantation. The gut microbiota was analyzed using 16S ribosomal DNA sequencing followed by absolute and relative quantitation analyses. Results: Nineteen genera were altered during glioma progression with the most dramatic changes in Firmicutes and Bacteroidetes phyla. During glioma growth, Lactobacillus abundance decreased at the earlier stage of glioma development (T1), and then gradually increased (T2, T3); Intestinimonas abundance exhibited a persistent increase; Anaerotruncus showed a transient increase and then a subsequent decrease. Twenty genera altered following TMZ treatment. The enrichment of Akkermansia and Bifidobacterium was observed only at the early stage following TMZ treatment (T2), but not at the later stage (T3). Additionally, the decrease of Anaerotruncus was slighter in TMZ group at T3 comparing to the vehicle group. The abundance of Intestinimonas increased constantly during the progression of glioma, but was unaffected by TMZ. Conclusions: Glioma development and progression resulted in altered gut microbiota. TMZ reversed the decrease of Anaerotruncus in glioma at T3, and increased the abundance of Bifidobacterium with no influence on the increase of Intestinimonas. Short-term and long-term effects of TMZ treatment on the bacterial communities may be differential. This study will improve understanding the role of gut microbiota in glioma, and help develop gut microbiota as a potential therapeutic target.

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Class I HDAC overexpression promotes temozolomide resistance in glioma cells by regulating RAD18 expression

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2022-04-01 | PXD028683 | Pride

Expression data from U-87 human glioma cells with proficient and deficient NF-кB after treatment with temozolomide

Project description:The transcription factor, NF-кB, plays a central role in the response to DNA damage. This ubiquitous family of proteins is made up of five subunits: p50 (NF-κB1, p105), p52 (NF-κB2, p100), p65 (relA), relB, and crel that appear in their mature form as dimers. Following stimulation, NF-κB dimers translocate to the nucleus where they bind specific consensus elements (κB-sites) in the promoter region of genes involved in cell survival, inflammation and the immune system. While there is a general propensity of NF-кB to mediate survival, this is not always the case and several reports note the pro-apoptotic nature of the NF-кB pathway. In examining the NF-кB response to DNA damage, we have found that the p50 subunit plays a central role in modulating cytotoxicity following TMZ treatment in malignant glioma. In the current study, given the importance of p50 to the cytotoxic response to TMZ, we set out to identify NF-кB-dependent factors that modulate the response to TMZ. U-87 glioma cells stably transfected with either control-shRNA or p105-shRNA and subsequently treated with temozolomide (TMZ) were selected for RNA extraction and hybridization on Affymetrix microarrays. Each category contains 3 biologic replicates.

2015-01-29 | E-GEOD-65363 | biostudies-arrayexpress

EGFR/FOXO3a/BIM signalling pathway determines chemosensitivity of BMP4-differentiated glioma stem cells to temozolomide

Project description:Accumulating evidence suggests that glioma stem cells (GSCs), rare cells characterised by pluripotency and self-renewal, are responsible for glioblastoma (GBM) propagation, recurrence and resistance to therapy. Differentiation with bone morphogenic proteins (BMPs) is considered to be a promising approach to eliminate GSCs and sensitise glioma to chemotherapeutics. Epidermal growth factor receptor (EGFR) gene alterations are detected in more than a half of GBMs, however, the role of EGFR in chemoresistance of glioma stem cells remain elusive. Here, we investigated whether EGFR signalling affects BMP4-induced differentiation of GSCs and their response to an alkylating drug temozolomide (TMZ). We show that BMP4 triggers Smad signalling cascade in glioma stem cells independently of the EGFR level. BMP4 down-regulated levels of pluripotency markers (SOX2 and OLIG2) with the concomitant induction of astrocytic (GFAP) and neuronal (b-Tubulin III) markers. However, significant differences in chemotherapy outcomes were observed in glioma stem cells with different EGFR levels. BMP4-induced differentiation did not enhance sensitivity to TMZ in EGFRlow GSCs, in contrast to EGFRhigh GSCs, which were undergoing apoptosis. We identified differences in cell cycle regulation by analyses of cell cycle phase distribution and cell-cycle-related proteins. In cells with lower EGFR expression BMP4 triggered the G1 cell cycle arrest, not detected in EGFRhigh cells. RNA-seq profiles further highlighted transcriptomic alternations and distinct processes characterizing EGFR-dependent responses in course of BMP4-induced differentiation. We identified AKT/FOXO3a axis controlling of BIM (the pro-apoptotic BCL-2 family protein) as operating only in EGFRhigh BMP4-differentiated and TMZ-treated cells.

2021-05-05 | GSE140441 | GEO

Transcriptomic analysis of the HOTAIR-regulated genes

Project description:An integrated RNA sequencing transcriptomic and quantitative proteomic analysis were employed to systematically explore the regulatory role of HOTAIR in HCC. A total of 673 transcripts and 298 proteins were identified to be dysregulated after HOTAIR inhibition.

2018-01-01 | GSE98091 | GEO

Microarray profiling analysis of lncRNAs expression in glioma cells

Project description:Tremendous studies have found that the abnormality of long noncoding RNA (lncRNA) contributed to cancer initiation, progression, and recurrence via multiple signaling cascades. Nevertheless, the possible underlying mechanisms of lncRNA in temozolomide (TMZ)-resistant glioma were not well understood, hindering the improvement of TMZ-based therapies against glioma. The present study illustrated that the lncRNA KCNQ1OT1 increased in TMZ-resistant gliomas cells compared to the parental cells. Introduction of KCNQ1OT1 boosted glioma cell viability, clonogenicity and rhodamine 123 efflux while hampered apoptosis post-exposure to TMZ. Consistent with bioinformatic prediction, KCNQ1OT1 directly sponged miR-761, which was downregulated in TMZ-resistant glioma cell lines. Overexpression of miR-761 attenuated glioma cell viability and clonogenicity while triggered apoptosis and rhodamine 123 cellular accumulation post-exposure to TMZ, leading to rehabilitated glioma TMZ-sensitivity, which was against the function of KCNQ1OT1. miR-761 bound to 3’-untranslated region of PIM1, a proto-oncogene with constitutive serine/threonine kinase activity, attenuated PIM1-mediated signaling cascades. Furthermore, stable knockdown of KCNQ1OT1 by small hairpin RNA amplified the TMZ-induced tumor regression in TMZ-resistant U251 mouse models. Briefly, the present study evaluated KCNQ1OT1 conferred TMZ resistance by sponging miR-761 and releasing PIM1 expression, resulting in activation of PIM-mediated MDR1/c-Myc/Survivin signaling pathways. The findings mentioned above extended the knowledge of lnRNA KCNQ1OT1 in the regulation of chemoresistance in glioma and provided a promising therapeutic target for TMZ-resistant glioma patients. Long noncoding RNA profiling by array

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