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Reversible LSD1 Inhibition with HCI-2509 induces the p53 gene expression signature in high-risk neuroblastoma cells

ABSTRACT: Lysine-Specific Demethylase 1 (LSD1) over-expression correlates with poorly differentiated neuroblastoma and predicts poor outcome despite multimodal therapy. We have studied the efficacy of reversible and specific LSD1 inhibition with HCI-2509 in neuroblastoma cell lines and particularly the effect of HCI-2509 on the transcriptomic profile in MYCN amplified NGP cells. Cell survival assays show that HCI-2509 is cytotoxic to poorly differentiated neuroblastoma cell lines in low micromole or lower doses. Transcriptional profiling of NGP cells treated with HCI-2509 shows a significant effect on p53, cell cycle, MYCN and hypoxia pathway gene sets. HCI-2509 results in increased histone methyl marks and p53 levels along with cell cycle arrest in the G2/M phase and inhibition of colony formation of NGP cells. Our findings indicate that LSD1 inhibition with HCI-2509 has a multi-target effect in MYCN amplified high-risk neuroblastoma cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE104526 | GEO | 2019/01/01

REPOSITORIES: GEO

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Expression data of A549 cells treated with 2 µM of HCI-2509 for 48 h

Project description:Inhibition of LSD1 is a novel option for treatment of lung cancer. Using HCI-2509, a specific inhibitor of LSD1, results in a cell cycle arrest as wel as a shift in global histone 3 lysine 4 and lysine 9 dimethylation pattern. Using microarrays we aim to illucidate the changed transcriptome upon treatement of HCI-2509 in lung adenocarcinoma cell line A549.

2017-08-30 | GSE103256 | GEO

Expression data of LUAD cell line PC9 treated with 2 uM HCI-2509 for 48 hours

Project description:The epigenetic regulator LSD1 is overepxpressed in lung adenocarcinoma (LUAD). HCI-2509 a LSD1 inhibitor leads to growth arrest in in vitro tumor models. To identify the underlying molecular mechanims behind LSD1 overexpression, we examined the gene expression patterns using microarray in the LUAD cell line PC9 after HCI-2509 treatment

2018-07-27 | GSE117702 | GEO

Genome-wide binding of MYCN protein in MYCN-amplified neuroblastoma cell lines

Project description:The MYCN locus is amplified in about half of high-risk neuroblastoma tumors. To identify genomic loci occupied by MYCN protein in the MYCN-amplified neuroblastoma cell lines NGP, Kelly and NB-1643, we performed chromatin immunoprecipitation coupled with Next-Generation Sequencing (ChIP-seq) using an anti-MYCN antibody.

2017-08-02 | GSE94782 | GEO

Reversible LSD1 Inhibition with HCI-2509 induces the p53 gene expression signature in high-risk neuroblastoma cells

Project description:Reversible LSD1 Inhibition with HCI-2509 induces the p53 gene expression signature in high-risk neuroblastoma cells

| PRJNA412925 | ENA

The Super Elongation Complex Drives Transcriptional Addiction in MYCN-amplified Neuroblastoma

Project description:MYCN amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which binds active genes promoting transcriptional amplification. Yet how MYCN coordinates transcription elongation to meet productive transcriptional amplification and which elongation machinery represents MYCN-driven vulnerability remain to be identified. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastomas. MYCN directly binds EAF1 and recruits SEC to enhance processive transcription elongation. Depletion of EAF1 or AFF1/AFF4, another core subunit of SEC, leads to a global reduction in transcription elongation and elicits selective apoptosis of MYCN-amplified neuroblastoma cells. A combination screen reveals SEC inhibition synergistically potentiates the therapeutic efficacies of FDA-approved BCL2 antagonist ABT-199, in part due to suppression of MCL1 expression, both in MYCN-amplified neuroblastoma cells and in patient-derived xenografts. These findings identify disruption of the MYCN-SEC regulatory axis as a promising therapeutic strategy in neuroblastoma.

2023-05-10 | PXD039332 | Pride

Inactivation of CDK2 is synthetic lethal to MYCN-overexpressing cancer cells

Project description:Two genes have a synthetic lethal relationship when silencing or inhibition of one gene is only lethal in the context of a mutation or activation of the second gene. This situation offers an attractive therapeutic strategy, as inhibition of such a gene will only trigger cell death in tumor cells with an activated second oncogene but spare normal cells without activation of the second oncogene. Here we present evidence that CDK2 is synthetic lethal to neuroblastoma cells with MYCN amplification and overexpression. Neuroblastomas are childhood tumors with an often lethal outcome. Twenty percent of the tumors have MYCN amplification and these tumors are ultimately refractory to any therapy. Targeted silencing of CDK2 by three RNA interference techniques induced apoptosis in MYCN-amplified neuroblastoma cell lines, but not in MYCN single copy cells. Silencing of MYCN abrogated this apoptotic response in MYCN-amplified cells. Inversely, silencing of CDK2 in MYCN single copy cells did not trigger apoptosis, unless a MYCN transgene was activated. The MYCN induced apoptosis after CDK2 silencing was accompanied by nuclear stabilization of P53 and mRNA profiling showed up-regulation of P53 target genes. Silencing of P53 rescued the cells from MYCN-driven apoptosis. The synthetic lethality of CDK2 silencing in MYCN activated neuroblastoma cells can also be triggered by inhibition of CDK2 with a small molecule drug. Treatment of neuroblastoma cells with Roscovitine, a CDK inhibitor, at clinically achievable concentrations induced MYCN-dependent apoptosis. The synthetic lethal relation between CDK2 and MYCN indicates CDK2 inhibitors as potential MYCN-selective cancer therapeutics. CDK2 shRNA in a tet repressor system was stably transfected in the IMR32 cell line. Time course analysis was performed in triplicate after induction of CDK2 shRNA at 5 time points.

2014-05-19 | E-GEOD-16480 | biostudies-arrayexpress

Direct interaction of MYCN and p53 regulate transcriptional responses in neuroblastoma [RNA-Seq]

Project description:The net transcriptome of a cancer cell is defined by relative levels of transcription factors, activators, suppressors and co-factors. These in turn are controlled by epigenetic, genetic and metabolic restraints. Here we used RNA-Seq, ChIP-qPCR, and ChIP-Seq to determine the impact of MYCN protein levels on p53 and MYCN mediated transcription in neuroblastoma, a p53 wild-type neural crest derived pediatric malignancy. Of note, about 25% of neuroblastoma is MYCN amplified and expresses 10-100 fold higher levels of MYCN protein than non-amplified tumors. We hypothesized that p53 functions would be globally altered by extreme MYCN levels and this could help to explain aggressive biology and poor long term survival which distinguishes MYCN-amplified neuroblastoma. In fact, we found that in the context of high MYCN levels, activation of p53 results in marked changes in transcription of specific p53 and MYCN target loci regulating apoptosis, DNA repair and cell cycle progression. Co-immunoprecipitation of endogenous and GST-fused proteins, as well as ChIP-qPCR confirms formation of p53/MYCN complexes and enrichment of both transcription factors at active loci. This p53/MYC interaction is independent of MYC/MAX complexes. Together, these data demonstrate MYCN to be a direct co-factor modulating p53 transcriptional output in MYCN amplified cancer.

2018-05-17 | GSE83327 | GEO

Direct interaction of MYCN and p53 regulate transcriptional responses in neuroblastoma [ChIP-Seq]

2018-05-17 | GSE83317 | GEO

Inactivation of CDK2 is synthetic lethal to MYCN-overexpressing cancer cells

2014-05-19 | GSE16480 | GEO

Metabolic dependencies in MYCN-driven neuroblastoma

Project description:Here we sought metabolic alterations specifically associated with amplified MYCN as nodes to indirectly target the MYCN oncogene. Liquid chromatography-mass spectrometry-based proteomics identified 7 proteins consistently correlated with MYCN in proteomes from 49 neuroblastoma biopsies and 13 cell lines. Among these were phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo serine synthesis. MYCN associated with two regions in the PHGDH promoter, supporting transcriptional PHGDH regulation by MYCN. Pulsed stable isotope-resolved metabolomics utilizing 13C-glucose labeling demonstrated higher de novo serine synthesis in MYCN-amplified cells compared to cells with diploid MYCN. An independence of MYCN-amplified cells from exogenous serine and glycine was demonstrated by serine and glycine starvation, which attenuated nucleotide pools and proliferation only in cells with diploid MYCN but did not diminish these endpoints in MYCN-amplified cells. Proliferation was attenuated in MYCN-amplified cells by CRISPR/Cas9-mediated PHGDH knockout or treatment with PHGDH small molecule inhibitors without affecting cell viability. PHGDH inhibitors administered as single-agent therapy to NMRI-Foxn1nu/nu mice harboring patient-derived MYCN-amplified neuroblastoma xenografts slowed tumor growth. However, combining a PHGDH inhibitor with the standard-of-care chemotherapy drug, cisplatin, revealed antagonism of chemotherapy efficacy in vivo. Emergence of chemotherapy resistance was confirmed in the genetic PHGDH knockout model in vitro. Altogether, PHDGH knockout and inhibition by small molecules consistently slows proliferation, but stops short of killing the cells, which then establish resistance to classical chemotherapy. Although PHGDH inhibition with small molecules has produced encouraging results in other preclinical cancer models, this approach must be considered with caution in patients with neuroblastoma.

2020-12-11 | PXD018300 | Pride

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