ETV4 coupled with p300-mediated histone lactylation drives thyroid cancer progression by activating autocrine TGFβ1 signaling

Papillary thyroid cancer (PTC) exhibits high morbidity and promising outcomes, but local advance and metastasis occasionally occur in the clinic with unknown mechanisms. E26 transformation-specific (ETS) domain protein ETV4 has been linked with various processes, including normal tissue development and tumorigenesis. However, the mechanism underlying ETV4-mediated tumorigenesis in PTC remains unclear. Here, we showed that ETV4 was predominantly expressed by PTC cancer cells and was associated with aggressive clinicopathological characteristics. Biological analyses showed that ETV4 served as an oncogene to promote PTC growth and metastasis by driving epithelial–mesenchymal transition (EMT) in vitro and in vivo . Mechanistically, ETV4 directly bound to the promoter of TGFB1 and recruited p300 to catalyze histone H3 lysine 18 lactylation (H3K18la) to synergistically increase chromatin accessibility around the TGFB1 promoter region, resulting in increased TGFB1 transcription and excessive secretion of TGFβ1 protein. In PTC cells, TGFβ1 activated the intracellular SMAD2/3 signaling pathway in an autocrine manner to induce the activation of the EMT-related transcriptional program and EMT-driven tumor progression. Pharmacologically, inhibition of the histone acyltransferase activity of p300 by a C646 inhibitor impaired the growth and metastatic ability of PTC by impeding p300–H3K18la-mediated TGFB1 transcription. Overall, these findings identify the oncogenic role of ETV4 in contributing to PTC progression and reveal a novel mechanism by which ETV4 cooperates with p300-mediated H3K18la to drive the transcription of specific target genes. This work provides insights into therapeutic strategies for PTC by targeting the functional connection between ETV4 and p300-mediated histone lactylation to drive autocrine TGFβ1 signaling activation.