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Metabolism of short‐chain fatty acid propionate induces surface expression of NKG2D ligands on cancer cells
Author(s) -
Høgh Rikke Illum,
Møller Sofie Hedlund,
Jepsen Stine Dam,
Mellergaard Maiken,
Lund Astrid,
Pejtersen Mikala,
Fitzner Emil,
Andresen Lars,
Skov Søren
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202000162r
Subject(s) - chemistry , propionate , metabolism , short chain fatty acid , biochemistry , fatty acid , fatty acid metabolism , butyrate , fermentation
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.