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Cannabinoid-driven epigenetic remodeling of a chromatin-lipid homeostatic axis via ARID1A uncovers a metabolic vulnerability in cancer

ABSTRACT: A substantial body of evidence supports a tumor suppressor role for the chromatin remodeler ARID1A, whose inactivating mutations and loss of function are common across human cancers. These alterations have spurred extensive efforts to uncover vulnerabilities associated with ARID1A deficiency. However, emerging studies suggest that ARID1A may also exert context-dependent tumor-promoting functions, opening new therapeutic avenues in ARID1A-proficient tumors. In endometrial cancer (EC), ARID1A mutations typically arise late during tumor progression and are dispensable for tumor initiation, providing a relevant context to interrogate its noncanonical homeostatic roles. Here, through integrated multiomics analyses, cellular bioenergetics and in vivo studies using EC patient-derived xenografts and genetically engineered mouse models, we demonstrate that functional ARID1A is required for acquired resistance to nutrient deprivation induced by antiangiogenic (starvation) therapy. Mechanistically, ARID1A orchestrates an epigenetically regulated chromatin-lipid homeostatic program involving lipid metabolism and mitochondrial fatty acid oxidation. Unexpectedly, we find that Δ9- tetrahydrocannabinol (THC), a phytocannabinoid and orthosteric CB1/CB2 agonist, exerts its antitumor activity by repressing ARID1A, thereby dismantling this chromatin- lipid metabolic axis and restoring sensitivity to starvation therapy. These findings position ARID1A as a central node linking chromatin remodeling to metabolic plasticity, and identify THC as a pharmacologic disruptor of this epigenetic metabolic program with therapeutic potential in ARID1A-proficient tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309010 | GEO | 2026/07/27

REPOSITORIES: GEO

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Project description:Extended periods of waking result in physiological impairments in humans, rats, and flies. Sleep homeostasis, the increase in sleep observed following sleep loss, is believed to counter the negative effects of prolonged waking by restoring vital biological processes that are degraded during sleep deprivation. Sleep homeostasis, as with other behaviors, is influenced by both genes and environment. We report here that during periods of starvation, flies remain spontaneously awake but, in contrast to sleep deprivation, do not accrue any of the negative consequences of prolonged waking. Specifically, the homeostatic response and learning impairments that are a characteristic of sleep loss are not observed following prolonged waking induced by starvation. To identify the genes responsible for the protective effects of starvation we conducted transcription profiling of sleep deprived flies that accrue sleep debt compared to starved siblings that do not. Genes involved in lipid metabolism were highly enriched in our dataset of 84 differentially regulated transcripts. Follow up genetic studies established that 6 genes involved in lipid metabolism strongly influence sleep homeostasis. Two of these genes, brummer (bmm) and Lipid storage droplet 2 (Lsd2), are in the same lipolysis pathway but exert antagonistic effects on lipid storage. bmm mutant flies have excess fat stores and display a large homeostatic response following sleep deprivation. In contrast, Lsd2 mutant flies, which phenocopy aspects of starvation as measured by low triglyceride stores, do not exhibit a homeostatic response following sleep loss. Importantly, Lsd2 mutant flies are not learning impaired after sleep deprivation. These results provide the first genetic evidence, to our knowledge, that lipid metabolism plays an important role in regulating the homeostatic response and can protect against neuronal impairments induced by prolonged waking. Two-condition experiments: sleep deprived vs starved. RNA from 8 biological replicates for each condition was pooled in groups of 2 to create 4 samples. Each of the 4 samples is run in duplicate with untreated circadian matched controls.

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Cannabinoid-driven epigenetic remodeling of a chromatin-lipid homeostatic axis via ARID1A uncovers a metabolic vulnerability in cancer

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