Centre for Genomics and Oncological Research (GENYO), Avenida de la Ilustración 114, 18016, Granada, Spain.
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain.
Cell Death Dis. 2024 Aug 22;15(8):609. doi: 10.1038/s41419-024-07011-y.
Emerging studies support that the polycomb repressive complex 2 (PRC2) regulates phenotypic changes of carcinoma cells by modulating their shifts among metastable states within the epithelial and mesenchymal spectrum. This new role of PRC2 in cancer has been recently proposed to stem from the ability of its catalytic subunit EZH2 to bind and modulate the transcription of mesenchymal genes during epithelial-mesenchymal transition (EMT) in lung cancer cells. Here, we asked whether this mechanism is conserved in other types of carcinomas. By combining TGF-β-mediated reversible induction of epithelial to mesenchymal transition and inhibition of EZH2 methyltransferase activity, we demonstrate that EZH2 represses a large set of mesenchymal genes and favours the residence of breast cancer cells towards the more epithelial spectrum during EMT. In agreement, analysis of human patient samples supports that EZH2 is required to efficiently repress mesenchymal genes in breast cancer tumours. Our results indicate that PRC2 operates through similar mechanisms in breast and lung cancer cells. We propose that PRC2-mediated direct transcriptional modulation of the mesenchymal gene expression programme is a conserved molecular mechanism underlying cell dissemination across human carcinomas.
新兴研究支持多梳抑制复合物 2 (PRC2) 通过调节上皮和间充质谱系中不稳定状态之间的转移来调节癌细胞的表型变化。PRC2 在癌症中的这一新作用最近被提出源于其催化亚基 EZH2 的能力，即在肺癌细胞上皮-间充质转化 (EMT) 过程中结合并调节间充质基因的转录。在这里，我们询问这种机制是否在其他类型的癌中保守。通过结合 TGF-β 介导的可逆诱导上皮向间充质转化和 EZH2 甲基转移酶活性的抑制，我们证明 EZH2 抑制一大组间充质基因，并有利于乳腺癌细胞在 EMT 过程中向更上皮谱系的居留。一致地，对人类患者样本的分析支持 EZH2 是在乳腺癌肿瘤中有效抑制间充质基因所必需的。我们的结果表明，PRC2 在乳腺癌和肺癌细胞中通过类似的机制发挥作用。我们提出 PRC2 介导的间充质基因表达程序的直接转录调节是人类癌中细胞扩散的保守分子机制。
