SCFAs are primarily produced in the colon by bacterial fermentation of nondigestible carbohydrates. Besides providing energy, SCFAs can suppress development of colon cancer. The mechanism, however, remains elusive. Here, we demonstrate that the SCFA propionate upregulates surface expression of the immune stimulatory NKG2D ligands, MICA/B by imposing metabolic changes in dividing cells. Propionate‐mediated MICA/B expression did not rely on GPR41/GPR43 receptors but depended on functional mitochondria. By siRNA‐directed knockdown, we could further link phosphoenolpyruvate carboxykinase (PEPCK), the rate‐limiting enzyme in gluconeogenesis to propionate regulation of MICA/B expression. Moreover, knockdown of Rictor and specific mTOR inhibitors implicated mTORC2 activity with metabolic changes that control MICA/B expression. SCFAs are precursors to short‐chain acyl‐CoAs that are used for histone acylation thereby linking the metabolic state to chromatin structure and gene expression. Propionate increased the overall acetylation and propionylation and inhibition of lysine acetyltransferases (KATs) that are responsible for adding acyl‐CoAs to histones reduced propionate‐mediated MICA/B expression, suggesting that propionate‐induced acylation increases MICA/B expression. Notably, propionate upregulated MICA/B surface expression on colon cancer cells in an acylation‐dependent manner; however, the impact of mitochondrial metabolism on MICA/B expression was different in colon cancer cells compared with Jurkat cells, suggesting that continuous exposure to propionate in the colon may provide an enhanced capacity to metabolize propionate. Together, our findings support that propionate causes metabolic changes resulting in NKG2D ligand surface expression, which holds potential as an immune activating anticancer therapy.

中文翻译：

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短链脂肪酸丙酸酯的代谢诱导癌细胞上NKG2D配体的表面表达

SCFA 主要在结肠中通过不易消化的碳水化合物的细菌发酵产生。除了提供能量外，SCFAs 还可以抑制结肠癌的发展。然而，该机制仍然难以捉摸。在这里，我们证明 SCFA 丙酸盐通过在分裂细胞中施加代谢变化来上调免疫刺激性 NKG2D 配体 MICA/B 的表面表达。丙酸盐介导的 MICA/B 表达不依赖于 GPR41/GPR43 受体，而是依赖于功能性线粒体。通过siRNA定向敲低，我们可以进一步将磷酸烯醇丙酮酸羧激酶（PEPCK）（糖异生中的限速酶）与MICA/B表达的丙酸调节联系起来。此外，Rictor 和特定 mTOR 抑制剂的敲低表明 mTORC2 活性与控制 MICA/B 表达的代谢变化有关。SCFA 是短链酰基辅酶 A 的前体，用于组蛋白酰化，从而将代谢状态与染色质结构和基因表达联系起来。丙酸盐增加了总体乙酰化和丙酰化，并抑制了赖氨酸乙酰转移酶 (KAT)，这些酶负责将酰基辅酶 A 添加到组蛋白中，从而降低了丙酸盐介导的 MICA/B 表达，表明丙酸盐诱导的酰化增加了 MICA/B 表达。值得注意的是，丙酸盐以酰化依赖性方式上调结肠癌细胞上的 MICA/B 表面表达；然而，与 Jurkat 细胞相比，结肠癌细胞中线粒体代谢对 MICA/B 表达的影响不同，这表明在结肠中持续暴露于丙酸盐可能会增强代谢丙酸盐的能力。一起，