A druggable cascade links methionine metabolism to epigenomic reprogramming in squamous cell carcinoma
Menée à l'aide de lignées cellulaires, d'organoïdes, de modèles murins et d'échantillons tumoraux issus de patients atteints d'un carcinome épidermoïde de la tête et du cou, cette étude met en évidence un lien mécanistique entre le métabolisme de la méthionine, le transporteur d'acides aminés LAT1 et l'enzyme EZH2 puis démontre que l'axe LAT1-méthionine-EZH2 est indispensable à la survie et à la prolifération des cellules cancéreuses et qu'il peut être bloqué par des approches pharmacologiques ou des interventions nutritionnelles
Upper aerodigestive squamous cell carcinoma (UASCC) is a common and aggressive malignancy with few effective therapeutic options. Here, we investigate amino acid metabolism in this cancer, surprisingly noting that UASCC exhibits the highest methionine level across all human cancers, driven by its transporter LAT1. We show that LAT1 is also expressed at the highest level in UASCC, transcriptionally activated by UASCC-specific promoter and enhancers, which are directly coregulated by SCC master regulators TP63/KLF5/SREBF1. Unexpectedly, unbiased bioinformatic screen identifies EZH2 as the most significant target downstream of the LAT1-methionine pathway, directly linking methionine metabolism to epigenomic reprogramming. Importantly, this cascade is indispensable for the survival and proliferation of UASCC patient-derived tumor organoids. In addition, LAT1 expression is closely associated with cellular sensitivity to inhibition of the LAT1-methionine-EZH2 axis. Notably, this unique LAT1-methionine-EZH2 cascade can be targeted effectively by either pharmacological approaches or dietary intervention in vivo. In summary, this work maps a unique mechanistic cross talk between epigenomic reprogramming with methionine metabolism, establishes its biological significance in the biology of UASCC, and identifies a unique tumor-specific vulnerability which can be exploited both pharmacologically and dietarily.
Proceedings of the National Academy of Sciences , résumé, 2023