Propionate reinforces epithelial identity and reduces aggressiveness of lung carcinoma

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 remodelling through H3K27 acetylation (mediated by p300) is the mechanism underlying the shift towards an epithelial state upon propionate treatment. The results suggest that propionate administration has therapeutic potential in reducing NSCLC aggressiveness and warrants further clinical testing.

上皮间质转化（epithelial-to-mesenchymal transition, EMT）在癌症转移与化疗耐药的发生发展中发挥核心作用，但其药物治疗仍面临诸多挑战。本研究采用聚焦EMT的整合功能基因组学方法，在非小细胞肺癌（non-small cell lung cancer, NSCLC）患者中鉴定出短链脂肪酸（丙酸盐与丁酸盐）与EMT之间的负相关关联。值得注意的是，体外丙酸盐处理可强化上皮转录程序，促进细胞间接触与细胞黏附，同时抑制肺癌细胞系中侵袭性及化疗耐药的EMT表型。丙酸盐处理还可降低裸鼠及基因工程非小细胞肺癌小鼠模型的转移潜能，限制淋巴结转移。进一步机制分析显示，经p300介导的H3K27乙酰化（H3K27 acetylation）实现的染色质重塑，是丙酸盐处理后细胞向上皮表型转变的核心机制。本研究结果表明，丙酸盐给药在降低非小细胞肺癌侵袭性方面具有治疗潜力，值得开展进一步的临床试验验证。