肝细胞癌（HCC）通常在炎症状态下展开，这是各种细胞因子的中心。更好地理解细胞因子的功能及其对疾病发展的贡献对未来的治疗策略和减少全球HCC负担至关重要。在这种情况下，HCC肿瘤环境中存在的主要细胞因子之一是转化生长因子-β（TGF-β）。它的一项经典功能涉及促进上皮-间充质转化（EMT），在肿瘤细胞中，促进侵袭性表型。尽管它具有临床相关性，但与TGF-β诱导的EMT及其分子调节相关的细胞事件尚不清楚。因此，在本研究的一部分中，我们用TGF-β处理了HCC细胞，并表征了与EMT相关的细胞过程。有趣的是，TGF-β触发的EMT被发现与细胞抑制和改变细胞代谢相关。TGF-β通过表观遗传学沉默导致细胞周期相关转录本的下调，如环A2（CCNA2）和代谢基因，如谷氨酸-草酰乙酸转氨酶1（GOT1）。TGF-β暴露后观察到总染色质抑制标记（H3K27me3）的增加以及具体丰富在CCNA2和GOT1上游启动子区域的H3K27me3的富集，从而导致它们的下调。重要的是，发现TGF-β下游信号介质-SMAD和染色质抑制复合物成员增强子锌指蛋白2（EZH2）共亚免疫沉淀，并需要上述影响。总体而言，我们的发现反映了HCC细胞进行EMT，获得细胞抑制和调节代谢需求，以有效促进EMT分化开关，并且这些事件通过TGF-β介导的信号在表观基因组水平上调节。我们的结果提供了更好的理解细胞侵袭特征，这可以导致开发新的治疗策略。©2023年作者。

Hepatocellular carcinoma (HCC) frequently unfolds under an inflammatory condition, which is a hub for a plethora of cytokines. A better understanding of the cytokine functions and their contributions to disease development is key to design of future therapeutic strategies and reduction of global HCC burden. In this context, one of the major cytokines present in the HCC tumour milieu is the transforming growth factor-β (TGF-β). One of its classical functions involve facilitation of epithelial to mesenchymal transition (EMT), in tumour cells, promoting an invasive phenotype. In spite of its clinical relevance, the cellular events associated with TGF-β-induced EMT and its molecular regulation is poorly elucidated. Therefore, as part of this study, we treated HCC cells with TGF-β and characterized the cellular processes associated with EMT. Interestingly, EMT triggered by TGF-β was found to be associated with cytostasis and altered cellular metabolism. TGF-β resulted in down-regulation of cell cycle-associated transcripts, like Cyclin A2 (CCNA2), and metabolic genes, like Glutamic-oxaloacetic transaminase 1 (GOT1) through epigenetic silencing. An overall increase in total histone repressive mark (H3K27me3) associated with a specific enrichment of H3K27me3 at the upstream promoter region of CCNA2 and GOT1 was observed after TGF-β exposure, leading to their down-regulation. Importantly, TGF-β-downstream signalling mediator- SMAD and chromatin repressive complex member-enhancer of zeste homolog 2 (EZH2) were found to co-immunoprecipitate and were required for the above effects. Overall, our findings reflect that HCC cells undergoing EMT, attain cytostasis and modulate metabolic demands to efficiently facilitate the EMT differentiation switch, and these events are regulated at the epigenomic level through TGF-β-mediated signalling. Our results provide better understanding of cellular invasive features which can lead to development of novel therapeutic strategies.© 2023 The Authors.