NOXA and RUNX1 in PDAC
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB39828 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR6558580_1.fastq.gz | Fastqsanger.gz | |||
| ERR6558580_2.fastq.gz | Fastqsanger.gz | |||
| ERR6558581_1.fastq.gz | Fastqsanger.gz | |||
| ERR6558581_2.fastq.gz | Fastqsanger.gz | |||
| ERR6558582_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 41 |
Similar Datasets
Project description:The ubiquitin-proteasome system (UPS) has recently emerged as a major target for drug development in cancer therapy. The proteasome inhibitor bortezomib has clinical activity in multiple myeloma and mantle cell lymphoma. Here we report that Eeyarestatin I (EerI), a chemical inhibitor that blocks ER-associated protein degradation (ERAD), has anti-tumor and biologic activities similar to bortezomib, and can synergize with bortezomib. Like bortezomib, EerI-induced cytotoxicity requires the upregulation of the BH3 only pro-apoptotic protein NOXA. We further demonstrate that both EerI and bortezomib activate NOXA via an unanticipated mechanism that requires cooperation between two processes: First, these agents elicit an integrated stress response program at the ER to activate the CREB/ATF transcription factors ATF3 and ATF4. We show that ATF3 and ATF4 form a complex capable of binding to the NOXA promoter, which is required for NOXA activation. Second, EerI and bortezomib also block ubiquitination of histone H2A to relieve its inhibition on NOXA transcription. Our results identify a class of anti-cancer agents that integrate ER stress response with an epigenetic mechanism to induce cell death.
2009-02-20 | GSE14003 | GEO
Project description:Oncogenic transcription factors such as the leukaemic fusion protein RUNX1/ETO constitute cancer-specific but highly challenging therapeutic targets, whose functions depend on pharmacologically tractable downstream pathways. Here we interrogated the transcriptional network of RUNX1/ETO in an in vitro/in vivo RNAi screen and identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO drives CCND2 expression by binding to a regulatory element upstream of the CCND2 promoter. Both knockdown of CCND2 and treatment with the CDK4/6 inhibitor palbociclib inhibited leukemic expansion patient-derived AML cells and impaired engraftment of immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO drives leukaemia by directly promoting cell cycle progression and establish inhibition of G1 CCND-CDK complexes as a promising therapeutic strategy for RUNX1/ETO-driven AML.
2019-04-12 | GSE117107 | GEO
Project description:Oncogenic transcription factors such as the leukaemic fusion protein RUNX1/ETO constitute cancer-specific but highly challenging therapeutic targets, whose functions depend on pharmacologically tractable downstream pathways. Here we interrogated the transcriptional network of RUNX1/ETO in an in vitro/in vivo RNAi screen and identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO drives CCND2 expression by binding to a regulatory element upstream of the CCND2 promoter. Both knockdown of CCND2 and treatment with the CDK4/6 inhibitor palbociclib inhibited leukemic expansion patient-derived AML cells and impaired engraftment of immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO drives leukaemia by directly promoting cell cycle progression and establish inhibition of G1 CCND-CDK complexes as a promising therapeutic strategy for RUNX1/ETO-driven AML.
2019-04-12 | GSE117105 | GEO
Project description:Our study delves into the intricate dynamics of the integrated stress response (ISR) axis, focusing on the pivotal role of PIM2 kinase and its interaction with the BCL2 family of proteins, revealing crucial mechanisms governing cell survival and tumor progression. Elevated PIM2 expression is a hallmark of various cancers, often correlating with disease aggressiveness. Using a model of normal and malignant plasma cells, we unveil that inhibiting PIM2 kinase triggers not only the production of phosphorylated BAD but also activates ISR-mediated NOXA expression. This shift towards heightened dependence on MCL1 underscores the synergy achieved through combined PIM/MCL1 inhibition, largely propelled by ISR-mediated NOXA expression. In mouse xenograft models, dual targeting of PIM2 and MCL1 effectively controls tumor growth, a response reversed by ISR-specific inhibition, concomitant with the upregulation of genes associated with tumor cell dissemination. These findings illuminate the molecular intricacies of PIM2 inhibition and its implications for cancer therapy, particularly in tumors marked by elevated PIM2 expression.
2024-11-29 | GSE266112 | GEO
Project description:Synthetic lethality by TET-dioxygenase inhibition
| PRJNA682029 | ENA
Project description:The ubiquitin-proteasome system (UPS) has recently emerged as a major target for drug development in cancer therapy. The proteasome inhibitor bortezomib has clinical activity in multiple myeloma and mantle cell lymphoma. Here we report that Eeyarestatin I (EerI), a chemical inhibitor that blocks ER-associated protein degradation (ERAD), has anti-tumor and biologic activities similar to bortezomib, and can synergize with bortezomib. Like bortezomib, EerI-induced cytotoxicity requires the upregulation of the BH3 only pro-apoptotic protein NOXA. We further demonstrate that both EerI and bortezomib activate NOXA via an unanticipated mechanism that requires cooperation between two processes: First, these agents elicit an integrated stress response program at the ER to activate the CREB/ATF transcription factors ATF3 and ATF4. We show that ATF3 and ATF4 form a complex capable of binding to the NOXA promoter, which is required for NOXA activation. Second, EerI and bortezomib also block ubiquitination of histone H2A to relieve its inhibition on NOXA transcription. Our results identify a class of anti-cancer agents that integrate ER stress response with an epigenetic mechanism to induce cell death. Experiment Overall Design: 1. EerI 10 vs 0 Experiment Overall Design: 2. EerI 10 vs 0 Experiment Overall Design: 3. Bzm 10 vs 0 Experiment Overall Design: 4. Bzm 10 vs 0
2009-02-28 | E-GEOD-14003 | biostudies-arrayexpress
Project description:Myc is an oncogenic transcription factor frequently dysregulated in human cancer. To identify pathways supporting the Myc oncogenic program, we employed a genome-wide RNAi screen for Myc-synthetic-lethal (MySL) genes and uncovered a role for the SUMO-activating-enzyme (SAE1/2). Loss of SAE1/2 enzymatic activity drives synthetic lethality with Myc. Mechanistically, SAE2 inhibition switches a transcriptional subprogram of Myc from activated to repressed. A subset of these SUMOylation-dependent Myc-switchers (SMS genes) governs mitotic spindle function and is required to support the Myc oncogenic program. comparison of 4 treatments: normal HMEC, High Myc in HMEC, SUMO depleted in HMEC, High Myc+Sumo Depleted in HMEC
2011-12-08 | E-GEOD-34055 | biostudies-arrayexpress
Project description:Bortezomib (BZM) is the first proteasome inhibitor approved for relapsed Mantle Cell Lymphoma (MCL) with durable responses seen in 30%-50% of patients. The biological basis for differences in response to BZM is not completely understood. Our previous work demonstrated marked differences in methylation between primary MCL and normal B cells. We hypothesized that a subset of aberrantly methylated genes may be modulating BZM response in MCL patients. We examined genome-wide DNA methylation profiles in MCL patient treated with BZM using a NimbleGen array platform. DNA methylation analysis revealed a striking promoter hypomethylation in MCL patient samples following BZM treatment. Pathway analysis of differentially methylated genes identified molecular mechanisms of cancer as a top canonical pathway enriched among hypomethylated genes in BZM treated samples. Noxa, a pro-apoptotic Bcl-2 family member essential for the cytotoxicity of BZM, was significantly hypomethylated and induced following BZM treatment. Therapeutically, we could demethylate Noxa and induce anti-lymphoma activity using BZM and the DNA methytransferase inhibitor Decitabine (DAC) and their combination in vitro and in vivo in BZM resistant MCL cells. Noxa depletion by RNA interference protected MCL cells from death by these agents. These findings suggest a role for dynamic Noxa methylation for therapeutic benefit of BZM. Potent and synergistic cytotoxicity between BZM and DAC in vitro and in vivo supports a strategy for using epigenetic priming to overcome BZM resistance in relapsed MCL patients. Our data demonstrate that genomic methylation profiling can provide mechanistic insights to guide novel therapeutic approaches.
2017-02-09 | GSE58165 | GEO
Project description:We performed CRISPR genome-wide synthetic lethality screens to identify genetic vulnerabilities and chemogenetic interactions in KRAS-driven pancreatic cancer. We identify ERAD as a genetic target that synergizes with FTS treatment and we show that FTS treatment induces ER stress, which was further enhanced by inhibition of ERAD, leading to synergistic induction of apoptosis in pancreatic tumor cells. Altogether, our screens enable us to identify combination therapies for cancer treatment.
2020-11-25 | GSE162065 | GEO
Project description:Ubiquitinated PCNA drives USP1 synthetic lethality in cancer
| PRJNA883979 | ENA