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Epigenetic and metabolic reprogramming by HDAC inhibition targets NRF2-active tumors

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE220839 | GEO | 2023/03/30

REPOSITORIES: GEO

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Epigenetic and metabolic reprogramming by HDAC inhibition targets NRF2-active tumors [RNA-Seq]

Project description:To investigate the NRF2-specific cytotoxic effects of HDAC inhibition, we assessed gene expression in the context of control and NRF2-overexpressing mouse LUAD cells upon HDAC inhibition.

2023-03-30 | GSE220837 | GEO

Epigenetic and metabolic reprogramming by HDAC inhibition targets NRF2-active tumors [CUT&Tag]

Project description:To investigate the NRF2-specific cytotoxic effects of HDAC inhibition, we assessed genomic distribution of histone acetylation modifications and readers in the context of control and NRF2-overexpressing mouse LUAD cells upon HDAC inhibition.

2023-03-30 | GSE220832 | GEO

Epigenetic and metabolic reprogramming by HDAC inhibition targets NRF2-active tumors [CRISPR Screen]

Project description:To identify NRF2-specific dependencies in chromatin regulation, we performed a focused genetic screen mouse LUAD cell lines with or without knock-out of KEAP1.

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Epigenetic and metabolic reprogramming by HDAC inhibition targets NRF2-active tumors

Project description:Epigenetic and metabolic reprogramming by HDAC inhibition targets NRF2-active tumors

| PRJNA911718 | ENA

Epigenetic and metabolic reprogramming by HDAC inhibition targets NRF2-active tumors [RNA-Seq]

Project description:Epigenetic and metabolic reprogramming by HDAC inhibition targets NRF2-active tumors [RNA-Seq]

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Epigenetic and metabolic reprogramming by HDAC inhibition targets NRF2-active tumors [CRISPR Screen]

Project description:Epigenetic and metabolic reprogramming by HDAC inhibition targets NRF2-active tumors [CRISPR Screen]

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Epigenetic and metabolic reprogramming by HDAC inhibition targets NRF2-active tumors [CUT&Tag]

Project description:Epigenetic and metabolic reprogramming by HDAC inhibition targets NRF2-active tumors [CUT&Tag]

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Metabolic reprogramming by histone deacetylase inhibition preferentially targets NRF2-activated tumors.

Project description:The interplay between metabolism and chromatin signaling is implicated in cancer progression. However, whether and how metabolic reprogramming in tumors generates chromatin vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor aberrant activation of the NRF2 antioxidant pathway, which drives aggressive and chemo-resistant disease. Using a chromatin-focused CRISPR screen, we report that NRF2 activation sensitizes LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDACs). This association is observed across cultured cells, mouse models, and patient-derived xenografts. Integrative epigenomic, transcriptomic, and metabolomic analysis demonstrates that HDAC inhibition causes widespread redistribution of H4ac and its reader protein, which transcriptionally downregulates metabolic enzymes. This results in reduced flux into amino acid metabolism and de novo nucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest NRF2 activation as a potential biomarker for effective repurposing of HDAC inhibitors to treat solid tumors.

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Genomic targets, and histone acetylation and gene expression profiling of neural HDAC inhibition

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-07-09 | E-GEOD-44868 | biostudies-arrayexpress

PI3Kδ/γ inhibition promotes human CART cell epigenetic and metabolic reprogramming to enhance antitumor cytotoxicity.

Project description:Current limitations in using chimeric antigen receptor T(CART) cells to treat patients with hematological cancers include limited expansion and persistence in vivo that contribute to cancer relapse. Patients with chronic lymphocytic leukemia (CLL) have terminally differentiated T cells with an exhausted phenotype and experience low complete response rates after autologous CART therapy. Because PI3K inhibitor therapy is associated with the development of T-cell-mediated autoimmunity, we studied the effects of inhibiting the PI3Kδ and PI3Kγ isoforms during the manufacture of CART cells prepared from patients with CLL. Dual PI3Kδ/γ inhibition normalized CD4/CD8 ratios and maximized the number of CD8+ T-stem cell memory, naive, and central memory T-cells with dose-dependent decreases in expression of the TIM-3 exhaustion marker. CART cells manufactured with duvelisib (Duv-CART cells) showed significantly increased in vitro cytotoxicity against CD19+ CLL targets caused by increased frequencies of CD8+ CART cells. Duv-CART cells had increased expression of the mitochondrial fusion protein MFN2, with an associated increase in the relative content of mitochondria. Duv-CART cells exhibited increased SIRT1 and TCF1/7 expression, which correlated with epigenetic reprograming of Duv-CART cells toward stem-like properties. After transfer to NOG mice engrafted with a human CLL cell line, Duv-CART cells expressing either a CD28 or 41BB costimulatory domain demonstrated significantly increased in vivo expansion of CD8+ CART cells, faster elimination of CLL, and longer persistence. Duv-CART cells significantly enhanced survival of CLL-bearing mice compared with conventionally manufactured CART cells. In summary, exposure of CART to a PI3Kδ/γ inhibitor during manufacturing enriched the CART product for CD8+ CART cells with stem-like qualities and enhanced efficacy in eliminating CLL in vivo.

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