LSD1 mediates AKT activity in PIK3CA mutant colorectal cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA587634 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10400200.fastq.gz | Fastqsanger.gz | |||
| SRR10400201.fastq.gz | Fastqsanger.gz | |||
| SRR10400202.fastq.gz | Fastqsanger.gz | |||
| SRR10400203.fastq.gz | Fastqsanger.gz | |||
| SRR10400204.fastq.gz | Fastqsanger.gz |
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Project description:Activation of the epithelial-mesenchymal transition (EMT) program is a critical mechanism for initiating cancer progression and migration. Colorectal cancers (CRCs) contain many genetic and epigenetic alterations that can contribute to EMT. Mutations activating the PI3K/AKT signaling pathway are observed in >40% of patients with CRC contributing to increased invasion and metastasis. Little is known about how oncogenic signaling pathways such as PI3K/AKT synergize with chromatin modifiers to activate the EMT program. Lysine Specific Demethylase 1 (LSD1) is a chromatin-modifying enzyme that is overexpressed in colorectal cancer (CRC) and enhances cell migration. In this study we determine that LSD1 expression is significantly elevated in CRC patients with mutation of the catalytic subunit of PI3K, PIK3CA, compared to CRC patients with WT PIK3CA. LSD1 enhances activation of the AKT kinase in CRC cells through a non-catalytic mechanism, acting as a scaffolding protein for the transcription-repressing CoREST complex. Additionally, growth of PIK3CA mutant CRC cells is uniquely dependent on LSD1. Knockdown or CRISPR knockout of LSD1 blocks AKT-mediated stabilization of the EMT-promoting transcription factor Snail and effectively blocks AKT-mediated EMT and migration. Overall we uniquely demonstrate that LSD1 mediates AKT activation in response to growth factors and oxidative stress, and LSD1-regulated AKT activity promotes EMT-like characteristics in a subset of PIK3CA mutant cells.
2019-11-06 | GSE139925 | GEO
Project description:Activation of the epithelial-mesenchymal transition (EMT) program is a critical mechanism for initiating cancer progression and migration. Colorectal cancers (CRCs) contain many genetic and epigenetic alterations that can contribute to EMT. Mutations activating the PI3K/AKT signaling pathway are observed in >40% of patients with CRC contributing to increased invasion and metastasis. Little is known about how oncogenic signaling pathways such as PI3K/AKT synergize with chromatin modifiers to activate the EMT program. Lysine Specific Demethylase 1 (LSD1) is a chromatin-modifying enzyme that is overexpressed in colorectal cancer (CRC) and enhances cell migration. In this study we determine that LSD1 expression is significantly elevated in CRC patients with mutation of the catalytic subunit of PI3K, PIK3CA, compared to CRC patients with WT PIK3CA. LSD1 enhances activation of the AKT kinase in CRC cells through a non-catalytic mechanism, acting as a scaffolding protein for the transcription-repressing CoREST complex. Additionally, growth of PIK3CA mutant CRC cells is uniquely dependent on LSD1. Knockdown or CRISPR knockout of LSD1 blocks AKT-mediated stabilization of the EMT-promoting transcription factor Snail and effectively blocks AKT-mediated EMT and migration. Overall we uniquely demonstrate that LSD1 mediates AKT activation in response to growth factors and oxidative stress, and LSD1-regulated AKT activity promotes EMT-like characteristics in a subset of PIK3CA mutant cells.
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Project description:LSD1 mediates AKT activity in PIK3CA mutant colorectal cancer [ChIP-Seq]
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Project description:LSD1 mediates AKT activity in PIK3CA mutant colorectal cancer [RNA-Seq]
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Project description:Olaparib and temozolomide (OT) combination therapy is in clinical trial evaluation foradolescent rhabdomyosarcoma (RMS) muscle cancers. Unfortunately, resistance to OT hasbeen reported in other cancers, with no counterstrategies available. Using preclinical mousexenograft experiments, we show that OT is effective at curbing RMS growth, yet a subset oftumors develop resistance that is associated with transcriptomic changes that occur in theabsence of recurrent genomic mutation. Importantly, a majority of resistant RMS modelsupregulate the PIK3CA/AKT pathway, which in turn activates NRF2 transcription factorphosphorylation and subsequent transcriptional expression of multidrug resistance ABCtransport proteins that rapidly efflux drugs from cells. We found that the PIK3CA inhibitoralpelisib re-sensitized resistant tumor cells to OT therapy by suppressing the expression of ABCtransport proteins. Excitingly, RMS use the same PIK3CA/AKT pathway activation to driveresistance to standard-of-care combination therapy vincristine, actinomycin D, andcyclophosphamide (VAC) and the combination of OT + alpelisib effectively killed VAC-resistantRMS. Alpelisib also re-sensitized resistant RMS to chemotherapy in preclinical xenograft mousemodels resulting in reduced tumor burden and extended disease-free survival. Our work definesa common resistance pathway in RMS and has credentialled a new preclinical strategy to killtherapy resistant RMS.
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Project description:Mutations in both RAS and the PTEN/PIK3CA/AKT signaling module are found in the same human tumors. PIK3CA and AKT are downstream effectors of RAS, and the selective advantage conferred by mutation of two genes in the same pathway is unclear. Based on a comparative molecular analysis, we show that activated PIK3CA/AKT is a weaker inducer of senescence than is activated RAS. More-over, concurrent activation of RAS and PIK3CA/AKT impairs RAS-induced senescence. We used microarrays to detail the global programme of gene expression after transduction of AKT and RAS IMR90 cells were transfected with Control, AKT and RAS retrovirus containing medium in 4 replicates. Fibroblasts were drug selected and kept in drug for duration of experiments.
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Project description:Mutations in both RAS and the PTEN/PIK3CA/AKT signaling module are found in the same human tumors. PIK3CA and AKT are downstream effectors of RAS, and the selective advantage conferred by mutation of two genes in the same pathway is unclear. Based on a comparative molecular analysis, we show that activated PIK3CA/AKT is a weaker inducer of senescence than is activated RAS. More-over, concurrent activation of RAS and PIK3CA/AKT impairs RAS-induced senescence. We used microarrays to detail the global programme of gene expression after transduction of AKT and RAS
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