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Sirtuin 2 inhibition selectively induces senescence in ATRX-deficient malignant gliomas by modulating chromatin landscapes genome-wide [RNA-Seq]

ABSTRACT: Sirtuin 2 inhibition selectively induces senescence in ATRX-deficient malignant gliomas by modulating chromatin landscapes genome-wide [RNA-Seq]

PROVIDER: PRJNA980744 | ENA |

REPOSITORIES: ENA

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Sirtuin 2 inhibition selectively induces senescence in ATRX-deficient malignant gliomas by modulating chromatin landscapes genome-wide

Project description:Sirtuin 2 inhibition selectively induces senescence in ATRX-deficient malignant gliomas by modulating chromatin landscapes genome-wide

| PRJNA980742 | ENA

Sirtuin 2 inhibition selectively induces senescence in ATRX-deficient malignant gliomas by modulating chromatin landscapes genome-wide [ChIP-Seq]

Project description:Sirtuin 2 inhibition selectively induces senescence in ATRX-deficient malignant gliomas by modulating chromatin landscapes genome-wide [ChIP-Seq]

| PRJNA980743 | ENA

Sirtuin 2 inhibition selectively induces senescence in ATRX-deficient malignant gliomas by modulating chromatin landscapes genome-wide [RNA-Seq]

Project description:To investigate the effect of SIRT2 inhibition on global transcriptomics profile, we inhibited Sirt2 using small molecules (AGK2) Our analysis reports phenotype-reversal of gliomas as well as induction of terminal differentiation program.

2023-06-15 | GSE234318 | GEO

Sirtuin 2 inhibition selectively induces senescence in ATRX-deficient malignant gliomas by modulating chromatin landscapes genome-wide [ChIP-Seq]

Project description:To investigate the effect of SIRT2 inhibition on global epigenome profile, we inhibited SIRT2 using AGK2 and performed ChIP-seq analysis for enhnacers, transcription and repressor histone marks Our analysis reports global epigenome changes that is responsible for phenotype-reversal of gliomas as well as induction of terminal differentiation program.

2023-06-15 | GSE234319 | GEO

Sirtuin 2 inhibition selectively induces senescence in ATRX-deficient malignant gliomas by modulating chromatin landscapes genome-wide

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-06-15 | GSE234320 | GEO

Synthetic lethal screen reveals selective vulnerability of ATRX-mutant cancers to WEE1 inhibition

Project description:we performed a genome-wide synthetic lethal screen, using CRISPR-Cas9 genome editing, to identify potential therapeutic targets specific for ATRX-mutated cancers. In isogenic hepatocellular carcinoma (HCC) cell lines engineered for ATRX loss, we identified 58 genes, including the checkpoint kinase WEE1, uniquely required for the cell growth of ATRX null cells. Treatment with the WEE1 inhibitor AZD1775 robustly inhibited the growth of several ATRX-deficient HCC cell lines in vitro, as well as xenografts in vivo. The increased sensitivity to the WEE1 inhibitor was caused by accumulated DNA damage induced apoptosis. AZD1775 also selectively inhibited the proliferation of patient-derived primary cell lines from gliomas with naturally occurring ATRX mutations, indicating that the synthetic lethal relationship between WEE1 and ATRX could be exploited in a broader spectrum of human tumors. As WEE1 inhibitors have been investigated in several phase II clinical trials, our discovery provides the basis for an easily clinically testable therapeutic strategy specific for cancers deficient in ATRX.

2019-10-23 | GSE114035 | GEO

G-quadruplex stabilizer CX-5461 effectively combines with ionizing radiation to selectively target ATRX-deficient malignant glioma [RNA-seq]

Project description:Mutational inactivation of α-thalassaemia/mental retardation X-linked (ATRX) represents a defining molecular feature in large subsets of adult and pediatric malignant glioma. ATRX deficiency gives rise to abnormal G-quadruplex (G4) DNA secondary structures at GC-rich regions of the genome, altering chromatin accessibility and enhancing DNA damage. Building on earlier work, we sought to assess the extent to which pharmacological G4 stabilization selectively enhances DNA damage and cell death in preclinical models of ATRX-deficient glioma. Deploying the G4 stabilizer CX-5461 in patient-derived glioma stem cells (GSCs) in vitro and in GSC murine flank and intracranial xenografts in vivo, we evaluated efficacy as both a single agent and in combination with ionizing radiation (IR), a central element of current treatment standards. CX-5461 promoted dose-sensitive lethality in ATRX-deficient GSCs relative to ATRX-intact controls. Mechanistic studies revealed that CX-5461 disrupted histone variant H3.3 deposition, enhanced replication stress and DNA damage pathways, activated p53-independent apoptosis, and induced G2/M arrest selectively in ATRX-deficient GSCs. These data were corroborated in vivo, where we notably demonstrated that combinational treatment leads to profound tumor growth delay and prolonged survival exclusively in ATRX-deficient flank tumors. In its totality, our work substantively demonstrates efficacy and defines mechanisms of action for a novel therapeutic strategy targeting ATRX-deficient malignant glioma, laying the groundwork for clinical translation.

2024-03-18 | GSE261563 | GEO

Atrx facilitate normal neuronal differentiation

Project description:Purpose: the chromatin-remodeler ATRX is frequently mutated in a range of human malignancies including pediatric and adult gliomas, and its loss underlies induction of alternative lengthening of telomeres (ALT) pathway for chromosome-end maintenance. But how ATRX exters its glioma suppresor role remains unclear. Here, we combine RNAi and somatic deletion approaches to demonstrate ATRX as a glioma suppressor controlling neural differentiation. Loss of ATRX promotes gliomagenesis by blocking neuronal progenitors from undergoing terminal maturation. Our findings provide the molecular and cellular mechanism underline ATRX's function in gliomagenesis.

2015-10-01 | GSE73447 | GEO

G-quadruplex stabilizer CX-5461 effectively combines with ionizing radiation to selectively target ATRX-deficient malignant glioma [CUT&Tag]

Project description:Mutational inactivation of ?-thalassaemia/mental retardation X-linked (ATRX) represents a defining molecular feature in large subsets of adult and pediatric malignant glioma. ATRX deficiency gives rise to abnormal G-quadruplex (G4) DNA secondary structures at GC-rich regions of the genome, altering chromatin accessibility and enhancing DNA damage. Building on earlier work, we sought to assess the extent to which pharmacological G4 stabilization selectively enhances DNA damage and cell death in preclinical models of ATRX-deficient glioma. To investigate the effect of G4 stabilization on histone variant H3.3 deposition on the genome, we treated patient-derived glioma stem cells (GSCs) with G4 stabilizer CX-5461 and performed cleavage under targets and tagmentation (CUT&Tag) for H3.3. Our analyses show that G4 stabilizer CX-541 disrupts H3.3 deposition in ATRX-deficient GSCs and likely enhances replication stress and DNA damage.

2024-03-18 | GSE261562 | GEO

Zebrafish Samples for Loss of ATRX cooperates with p53-Deficiency to promote the Development of Sarcomas and other Malignancies

Project description:The SWI/SNF-family chromatin remodeling protein ATRX is a tumor suppressor in sarcomas, gliomas and other malignancies. Its loss of function facilitates the alternative lengthening of telomeres (ALT) pathway in tumor cells, while it also affects Polycomb repressive complex 2 (PRC2) silencing of its target genes. To further define the role of inactivating ATRX mutations in carcinogenesis, we knocked out atrx in our previously published p53/nf1-deficient zebrafish line that develops malignant peripheral nerve sheath tumors and gliomas. Complete inactivation of atrx using CRISPR-cas9 was lethal in developing fish and resulted in an alpha-thalassemia-like phenotype including reduced alpha-globin expression. In p53/nf1-deficient zebrafish neither peripheral nerve sheath tumors nor gliomas showed accelerated onset in atrx+/- fish, but these fish developed various tumors that were not observed in their atrx+/+ siblings, including epithelioid sarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma and rare types of carcinoma. Most of these cancer types are included in the AACR Genie database of human tumors associated with mutant ATRX, indicating that our zebrafish model reliably reflects a role for ATRX-loss in the early pathogenesis of these types of human cancers. RNA-seq of p53/nf1- and p53/nf1/atrx-deficient tumors revealed that down-regulation of telomerase accompanied ALT-mediated lengthening of the telomeres in atrx-mutant samples. Moreover, inactivating mutations in atrx disturbed PRC2-target gene silencing, indicating a connection between ATRX loss and PRC2 dysfunction in cancer development.

2019-02-15 | GSE125040 | GEO

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