Short-chain fatty acids activate acetyltransferase p300

Thomas, Sydney P.; Denu, John M.

doi:10.1101/2021.07.21.453192

Cited by 9 publications

(10 citation statements)

References 119 publications

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“…8a-c) . Additionally, we detected increases in several other acyl-CoA species including butyryl-CoA, which has recently been shown to augment CBP/p300 activity 43 (Extended Data Fig. 8b,c) .…”

Section: Resultsmentioning

confidence: 56%

Metabolic adaptations underpin resistance to histone acetyltransferase inhibition

Bishop

Subramanian

Bilotta

et al. 2022

Preprint

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Histone acetyltransferases (HAT) catalyze the acylation of lysine side chains and are implicated in diverse human cancers as both oncogenes and non-oncogene dependencies1. Acetyl-CoA-competitive HAT inhibitors have garnered attention as potential cancer therapeutics and the first clinical trial for this class is ongoing (NCT04606446). Despite broad enthusiasm for these targets, notably including CBP/p300 and KAT6A/B2-5, the potential mechanisms of therapeutic response and evolved drug resistance remain poorly understood. Using comparative transcriptional genomics, we found that the direct gene regulatory consequences of CBP/p300 HAT inhibition are indistinguishable in models of intrinsically hypersensitive and insensitive acute myeloid leukemia (AML). We therefore modelled acquired drug resistance using a forward genetic selection and identified dysregulation of coenzyme A (CoA) metabolism as a facile driver of resistance to HAT inhibitors. Specifically, drug resistance selected for mutations in PANK3, a pantothenate kinase that controls the rate limiting step in CoA biosynthesis6. These mutations prevent negative feedback inhibition, resulting in drastically elevated concentrations of intracellular acetyl-CoA, which directly outcompetes drug-target engagement. This not only impacts the activity of structurally diverse CBP/p300 HAT inhibitors, but also agents related to an investigational KAT6A/B inhibitor that is currently in Phase-1 clinical trials. We further validated these results using a genome-scale CRISPR/Cas9 loss-of-function genetic modifier screen, which identified additional gene-drug interactions between HAT inhibitors and the CoA biosynthetic pathway. Top hits from the screen included the phosphatase, PANK4, which negatively regulates CoA production and therefore suppresses sensitivity to HAT inhibition upon knockout7, as well as the pantothenate transporter, SLC5A68, which enhances sensitivity. Altogether, this work uncovers CoA plasticity as an unexpected but potentially class-wide liability of anti-cancer HAT inhibitors and will therefore buoy future efforts to optimize the efficacy of this new form of targeted therapy.

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Section: Resultsmentioning

confidence: 56%

Metabolic adaptations underpin resistance to histone acetyltransferase inhibition

Bishop

Subramanian

Bilotta

et al. 2022

Preprint

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“…We show that melanoma cells can employ mcFA-derived acetyl-CoA for global histone acetylation, whereas blockade of the FAO (HADHA and ACAA2)-ACLY axis hinders octanoate-mediated histone acetylation. In addition, octanoate-induced histone acetylation can be blunted by pharmacological inhibition of p300 activity, echoing a recent finding that short-chain fatty acids (scFAs) could directly activate p300 (Thomas and Denu, 2021). However, the selectivity of p300 as a major HAT driven by mcFAs could also be determined by acetyl-CoA concentrations (Pietrocola et al, 2015) or cooperation with its transcriptional cofactors or binding partners.…”

Section: Discussionmentioning

confidence: 89%

Epigenetic reprogramming of melanoma cell state through fatty acid β-oxidation and Toll-like receptor 4 signaling

Huang

Montal

et al. 2022

Preprint

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Tumor cells respond to a host of factors from the local microenvironment. Microenvironmental fatty acids can be used by melanoma cells for fuel, but their effects on transcription and epigenetics are still unclear. Here, we show that the fatty acid β-oxidation (FAO) pathway integrates signaling and epigenetics to drive melanoma progression. Using transgenic zebrafish and human cell lines, we find that octanoate, a medium-chain fatty acid, increases tumorigenesis. Octanoate is metabolized via the FAO/ACLY axis into acetyl-CoA, leading to increased histone acetylation. Transcriptomic and epigenetic analyses demonstrate a convergence of inflammatory gene signatures in octanoate-treated melanoma cells. This signature is mediated by TLR4/MyD88 signaling, which is activated by saturated fatty acids like octanoate. Genetic inactivation of either FAO enzymes or TLR4/MyD88 inhibits alterations in histone acetylation, and rescues octanoate tumor promoting effects. Together, these data demonstrate clear evidence linking fatty acid metabolism and epigenetics to melanoma pathogenesis through TLR4 signaling.

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“…We tested the spheroids responsiveness to drug treatment and demonstrate that, upon exposure, they respond to stimulation by changing the metabolism and chromatin dynamics. By treating spheroids with a drug that yields acetyl-CoA metabolites, we observed changes in histone acetylation, which triggers chromatin state rearrangements [36]. The modulation of transcription through core histone acetylation is one of the most relevant mechanisms by which cell are epigenetically regulated [37].…”

Section: Discussionmentioning

confidence: 99%

Investigation of reversible histone acetylation and dynamics in gene expression regulation using 3D liver spheroid model

Stransky

Cutler

Aguilan

et al. 2022

Preprint

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Background: Three-dimensional (3D) cell culture has emerged as an alternative approach to 2D flat culture to model more accurately the phenotype of solid tissue in laboratories. Culturing cells in 3D more precisely recapitulates physiological conditions of tissues, as these cells reduce activities related to proliferation, focusing their energy consumption towards metabolism and homeostasis. Results: Here, we demonstrate that 3D liver spheroids are a suitable system to model chromatin dynamics and response to epigenetics inhibitors. To delay necrotic tissue formation despite proliferation arrest, we utilize rotating bioreactors that apply active media diffusion and low shearing forces. We demonstrate that the proteome and the metabolome of our model resemble typical liver functions. We prove that spheroids respond to sodium butyrate (NaBut) treatment, an inhibitor of histone deacetylases (HDACi), by upregulating histone acetylations and transcriptional activation. As expected, NaBut treatment impaired specific cellular functions, including the energy metabolism. More importantly, we demonstrate that spheroids reestablish their original proteome and transcriptome, including pre-treatment levels of histone acetylation, metabolism, and protein expression once the standard culture condition is restored after treatment. Given the slow replication rate (>40 days) of cells in 3D spheroids, our model enables to monitor the recovery of approximately the same cells that underwent treatment, demonstrating that NaBut does not have long-lasting effects on histone acetylation and gene expression. These results suggest that histone acetylation has minimal epigenetics memory in our spheroids culture. Conclusion: Together, we established an innovative cell culture system that can be used to model anomalously decondensing chromatin in physiological cell growth and rule out epigenetics inheritance if cells recover the original phenotype after treatment. The transient epigenetics effects demonstrated here highlights the relevance of using a 3D culture model system that could be very useful in studies requiring long term drug treatment conditions that would not be possible using a 2D cell monolayer system.

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Short-chain fatty acids activate acetyltransferase p300

Cited by 9 publications

References 119 publications

Metabolic adaptations underpin resistance to histone acetyltransferase inhibition

Metabolic adaptations underpin resistance to histone acetyltransferase inhibition

Epigenetic reprogramming of melanoma cell state through fatty acid β-oxidation and Toll-like receptor 4 signaling

Investigation of reversible histone acetylation and dynamics in gene expression regulation using 3D liver spheroid model

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