The epithelial-to-mesenchymal transition (EMT) plays a central role in the development of cancer metastasis and resistance to chemotherapy. However, its pharmacological treatment remains challenging. Here, we used an EMT-focused integrative functional genomic approach and identified an inverse association between short-chain fatty acids (propionate and butanoate) and EMT in non-small cell lung cancer (NSCLC) patients. Remarkably, treatment with propionate in vitro reinforced the epithelial transcriptional program promoting cell-to-cell contact and cell adhesion, while reducing the aggressive and chemo-resistant EMT phenotype in lung cancer cell lines. Propionate treatment also decreased the metastatic potential and limited lymph node spread in both nude mice and a genetic NSCLC mouse model. Further analysis revealed that chromatin remodeling through H3K27 acetylation (mediated by p300) is the mechanism underlying the shift toward an epithelial state upon propionate treatment. The results suggest that propionate administration has therapeutic potential in reducing NSCLC aggressiveness and warrants further clinical testing.

中文翻译：

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丙酸盐增强上皮细胞特性并降低肺癌的侵袭性

上皮间质转化（EMT）在癌症转移和化疗耐药的发展中发挥着核心作用。然而，其药物治疗仍然具有挑战性。在这里，我们使用了以 EMT 为重点的综合功能基因组方法，并确定了非小细胞肺癌 (NSCLC) 患者中短链脂肪酸（丙酸和丁酸）与 EMT 之间的负相关关系。值得注意的是，体外丙酸盐治疗增强了上皮转录程序，促进细胞间接触和细胞粘附，同时减少肺癌细胞系中的侵袭性和化疗耐药性 EMT 表型。丙酸盐治疗还降低了裸鼠和遗传性非小细胞肺癌小鼠模型的转移潜力并限制了淋巴结扩散。进一步的分析表明，通过 H3K27 乙酰化（由 p300 介导）的染色质重塑是丙酸盐处理后向上皮状态转变的机制。结果表明，丙酸盐给药具有降低 NSCLC 侵袭性的治疗潜力，值得进一步的临床测试。