ROR alpha Regulates Cholesterol Metabolism of CD8(+) T Cells for Anticancer Immunity
- Authors
- Lee, In Kyu; Song, Hyerin; Kim, Hyerim; Kim, Ik Soo; Na Ly Tran; Kim, Sang-Heon; Oh, Seung Ja; Lee, Ji Min
- Issue Date
- Jul-2020
- Publisher
- MDPI
- Keywords
- Cholesterol; CD8(+)T cell; ROR alpha; NF-kappa B
- Citation
- CANCERS, v.12, no.7
- Journal Title
- CANCERS
- Volume
- 12
- Number
- 7
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/80078
- DOI
- 10.3390/cancers12071733
- ISSN
- 2072-6694
- Abstract
- Retinoic acid-related orphan receptor alpha (ROR alpha) functions as a transcription factor for various biological processes, including circadian rhythm, inflammation, cancer, and lipid metabolism. Here, we demonstrate that ROR alpha is crucial for maintaining cholesterol homeostasis in CD8(+)T cells by attenuating NF-kappa B transcriptional activity. Cholesterol sulfate, the established natural agonist of ROR alpha, exhibits cellular cytotoxicity on, and increased effector responses in, CD8(+)T cells. Transcript analysis reveals that the suppression of ROR alpha leads to the upregulation of NF-kappa B target genes in T cells. Chromatin immunoprecipitation analysis was used to determine the corecruitment of ROR alpha and histone deacetylase (HDAC) on NF-kappa B target promoters and the subsequent dismissal of coactivators for transcriptional repression. We demonstrate that ROR alpha/HDAC-mediated attenuation of NF-kappa B signaling controls the balance of cholesterol metabolism in CD8(+)T cells, and that therapeutic strategies targeting this epigenetic regulation could be beneficial to the treatment of solid tumors including colon cancers.
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