Epigenetic and metabolic reprogramming by HDAC inhibition targets NRF2-active tumors [RNA-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE220837 | GEO | 2023/03/30
REPOSITORIES: GEO
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Project description:Transcriptional profiling of BL/6 mice harboring a mutant Kras allele, with or without knockouts of Stk11 and/or Keap1, or with expression of an Nfe2l2 transgene, Nrf2Tg. In lung adenocarcinoma (LUAD), stabilization of the transcription factor NRF2 through genomic alterations in KEAP1 and NFE2L2 occurs in roughly a quarter of patients, often in the context of STK11 tumor suppressor loss. In this study, we demonstrate that NRF2 activation in the context of concurrent KRAS mutation and STK11 loss promotes aggressive LUAD tumor behavior in both human and mouse preclinical models. This phenotype is associated with metabolic rewiring and rescue by NRF2 of redox stress, high in STK11 null tumors. Applying a novel, pan-lung cancer, diagnostic NRF2 activation gene expression signature that is independent of frequently co-occurring mutations, we dissect the independent contributions of the three most frequent genetic events in human LUAD (NRF2 activation, STK11 loss and KRAS mutations) on patient prognosis and clinical responses in a dataset of second-line LUAD patients treated with immunotherapy or chemotherapy (OAK trial). Our findings underscore that both individual effects and epistatic relationships among oncogenic and tumor suppressor pathways influence tumor biology, immune contexture and patient clinical outcomes. Our work also highlights the value of lung cancer disease sub-classification based on genetic and expression profiling as part of patient clinical management.
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Project description:Histone deacetylase (HDAC) inhibitors are part of a new generation of epigenetic drugs for cancer treatment. It is known that histone acetylation plays a key role in controlling essential chromosome functions, including gene regulation, and this process has been linked with cancer development and progression. Better understanding of molecular mechanisms involving HDAC inhibitors is needed for the design of new targeted drugs, and also to evaluate the effectiveness of current treatments. In this study, an untargeted metabolomics approach was used to identify intracellular metabolite deregulation after treating cancer cell lines with the HDAC inhibitor HC-Toxin. Metabolomics analysis was performed using high resolution mass spectrometry, in combination with univariate and multivariate statistics and pathway analysis. HDAC inhibition showed highly specific metabolic changes in cancer cell lines compared to non-cancerous cells. In particular, N-acetyl-L-cysteine, N-acetylmethionine, and N-acetyl-L-carnitine showed a dose dependent change. Moreover, pathways controlling protein biosynthesis, as well as tryptophan, cysteine and methionine metabolism were significantly altered by HDAC inhibition. This study illustrates that HDAC inhibition has multiple effects on different metabolic pathways and our results can be extrapolated to inform on the molecular transitions in human cells.
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Project description:Ixazomib has documented pre-clinical activity in T cell (TCL) and Hodgkin (HL) lymphoma models with transcriptomic analyses predicting synergistic activity in combination with histone deacetylase (HDAC) inhibition. In the present study, we determined the mechanistic basis for synergism with ixazomib in combination with the HDAC inhibitor, belinostat, in HL and TCL cells lines (ixazomib-sensitive and -resistant clones) and primary tumor cells. In ixazomib-treated TCL and HL cells, we observed induction of proteasomal gene expression and NRF2 as a prominent upstream regulator. Ixazomib treatment in TCL and HL cells resulted in transient inhibition followed by full recovery of proteasomal activity within 72 hours. Furthermore, transcriptomic analysis following belinostat treatment resulted in downregulation of both NRF2 and proteasomal gene expression (validated by qPCR) without direct impact on proteasomal activity in Jurkat and L428. In addition, CRISPR/Cas9 mediated knockdown of NRF2 in Jurkat cells resulted in a significant decrease in cell viability with ixazomib compared with untreated control cells. Using transcriptomic and proteosomal activity evaluation of ixazomib, belinostat or ixazomib+belinostat treated cells, we observed that NRF-2, proteasome gene expression and functional recovery were abrogated by the combination. We also confirmed that ixazomib/belinostat resulted in synergistic activity in ixazomib-sensitive and -resistant cell lines and primary cells. Altogether, these results suggest that the synergistic activity of ixazomib and belinostat is mediated via inhibition NRF2-dependent proteasomal recovery and extended proteasomal inhibition culminating in increased cell death. Further investigation is warranted to determine the full biological role for NRF2 as a response modifier in proteasomal targeted therapies.
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The integrated base model of NRF2–p53 oxidative-stress signaling contains 42 reactions and 22 ordinary differential equations (ODEs).
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