Lactylation-induced TRIM47 exacerbates cell viability, cell cycle progression, and glycolysis in thyroid cancer by inducing ubiquitin-mediated degradation of FBP1

Lactic acid-mediated histone lactylation regulates cancer-related gene expression, but its role in thyroid Cancer remains unclear. We investigated E3 Ligase TRIM47's oncogenic function and its regulation via lactylation-mediated feedback in thyroid carcinogenesis. TRIM47 expression was analyzed in clinical specimens with clinicopathological correlation. Functional studies included TRIM47 knockdown (assessing viability, glycolysis, and xenograft growth) and rescue experiments (the glycolysis inhibitor 2-DG or fructose-1,6-bisphosphatase 1 (FBP1) overexpression vector co-treatment with TRIM47 overexpression). The binding between TRIM47 and FBP1 was analyzed using co-immunoprecipitation. FBP1 ubiquitination was detected using immunoprecipitation and Western blotting. Furthermore, lactic acid-treated Cancer cells were subjected to analysis of H3K18la, TRIM47, and FBP1 expression levels, combined with chromatin immunoprecipitation (ChIP) assays to elucidate the critical role of histone lactylation in the TRIM47-FBP1 signaling axis. TRIM47 expression was significantly upregulated in thyroid Cancer tissues. Genetic knockdown of TRIM47 effectively inhibited Cancer cellular viability, cell cycle advancement, glycolytic activity, and the growth of xenograft tumors in vivo. The oncogenic phenotypes driven by TRIM47 overexpression on cellular viability and the cell cycle were counteracted by either administration of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) or by forced expression of FBP1. Mechanistically, TRIM47 induced ubiquitin-mediated degradation of FBP1. Lactic acid treatment upregulated both TRIM47 expression and H3K18 lactylation (H3K18la), while downregulating FBP1 expression. ChIP assays demonstrated enrichment of H3K18la at the TRIM47 promoter region. Furthermore, treatment with the lactylation inhibitor oxamate suppressed TRIM47 and H3K18la expression while restoring FBP1 expression levels. As the core effector molecule in the lactic acid-H3K18la epigenetic circuit, TRIM47 drives tumorigenesis by inducing ubiquitin-mediated degradation of FBP1. Targeting of this signaling axis holds significant promise for the development of new thyroid Cancer therapies.