MT1G induces lipid droplet accumulation through modulation of H3K14 trimethylation accelerating clear cell renal cell carcinoma progression
Menée à l'aide de lignées cellulaires de carcinomes rénaux à cellules claires, de tissus tumoraux, de modèles murins et de données issues de bases génomiques, cette étude met en évidence un mécanisme par lequel la métallothionéine MT1G favorise la progression tumorale en induisant l'accumulation de gouttelettes lipidiques via la suppression de la triméthylation de la lysine 14 de l'histone 3 et l'inhibition de l'expression de la carnitine palmitoyltransférase CPT1B
Background : Lipid droplet formation is a prominent histological feature in clear cell renal cell carcinoma (ccRCC), but the significance and mechanisms underlying lipid droplet accumulation remain unclear.
Methods : Expression and clinical significance of MT1G in ccRCC were analyzed by using TCGA data, GEO data and scRNASeq data. MT1G overexpression or knockdown ccRCC cell lines were constructed and in situ ccRCC model, lung metastasis assay, metabolomics and lipid droplets staining were performed to explore the role of MT1G on lipid droplet accumulation in ccRCC.
Results : Initially, we observed low MT1G expression in ccRCC tissues, whereas high MT1G expression correlated with advanced disease stage and poorer prognosis. Elevated MT1G expression promoted ccRCC growth and metastasis both in vitro and in vivo. Mechanistically, MT1G significantly suppressed acylcarnitine levels and downstream tricarboxylic acid (TCA) cycle activity, resulting in increased fatty acid and lipid accumulation without affecting cholesterol metabolism. Notably, MT1G inhibited H3K14 trimethylation (H3K14me3) modification. Under these conditions, MT1G-mediated H3K14me3 was recruited to the CPT1B promoter through direct interaction with specific promoter regions, leading to reduced CPT1B transcription and translation.
Conclusions : Our study unveils a novel mechanism of lipid droplet accumulation in ccRCC, where MT1G inhibits CPT1B expression through modulation of H3K14 trimethylation, consequently enhancing lipid droplet accumulation and promoting ccRCC progression.
British Journal of Cancer , article en libre accès, 2024