MUC1-C is a master regulator of MICA/B NKG2D ligand and exosome secretion in human cancer cells

by Selleckchem | Aug 20 2023

Background: The MUC1-C protein evolved in mammals to protect barrier tissues from loss of homeostasis; however, MUC1-C promotes oncogenesis in association with chronic inflammation. Aberrant expression of MUC1-C in cancers has been linked to depletion and dysfunction of T cells in the tumor microenvironment. In contrast, there is no known involvement of MUC1-C in the regulation of natural killer (NK) cell function.

Methods: Targeting MUC1-C genetically and pharmacologically in cancer cells was performed to assess effects on intracellular and cell surface expression of the MHC class I chain-related polypeptide A (MICA) and MICB ligands. The MICA/B promoters were analyzed for H3K27 and DNA methylation. Shedding of MICA/B was determined by ELISA. MUC1-C interactions with ERp5 and RAB27A were assessed by coimmunoprecipitation and direct binding studies. Exosomes were isolated for analysis of secretion. Purified NK cells were assayed for killing of cancer cell targets.

Results: Our studies demonstrate that MUC1-C represses expression of the MICA and MICB ligands that activate the NK group 2D receptor. We show that the inflammatory MUC1-C→NF-κB pathway drives enhancer of zeste homolog 2-mediated and DNMT-mediated methylation of the MICA and MICB promoter regions. Targeting MUC1-C genetically and pharmacologically with the GO-203 inhibitor induced intracellular and cell surface MICA/B expression but not MICA/B cleavage. Mechanistically, MUC1-C regulates the ERp5 thiol oxidoreductase that is necessary for MICA/B protease digestion and shedding. In addition, MUC1-C interacts with the RAB27A protein, which is required for exosome formation and secretion. As a result, targeting MUC1-C markedly inhibited secretion of exosomes expressing MICA/B. In concert with these results, we show that targeting MUC1-C promotes NK cell-mediated killing.

Conclusions: These findings uncover pleotropic mechanisms by which MUC1-C confers evasion of cancer cells to NK cell recognition and destruction.

Comments:

The background information you provided suggests that the MUC1-C protein, which evolved in mammals to protect barrier tissues, can promote oncogenesis in the presence of chronic inflammation. Aberrant expression of MUC1-C in cancers has been associated with the depletion and dysfunction of T cells in the tumor microenvironment. However, its involvement in the regulation of natural killer (NK) cell function was not previously known.

In the study you described, the researchers targeted MUC1-C genetically and pharmacologically in cancer cells to investigate its effects on the expression of MHC class I chain-related polypeptide A (MICA) and MICB ligands. These ligands are important for activating the NK group 2D receptor, which plays a role in NK cell recognition and killing of cancer cells. The researchers analyzed the MICA/B promoters and found that MUC1-C, through the inflammatory MUC1-C→NF-κB pathway, contributes to the methylation of the MICA and MICB promoter regions by involving the enhancer of zeste homolog 2 and DNA methyltransferases.

By targeting MUC1-C genetically and using a specific inhibitor called GO-203, the researchers were able to increase the expression of intracellular and cell surface MICA/B without affecting their cleavage. They discovered that MUC1-C regulates the ERp5 thiol oxidoreductase, which is necessary for the digestion and shedding of MICA/B. Additionally, MUC1-C interacts with the RAB27A protein, which is involved in exosome formation and secretion. Targeting MUC1-C resulted in decreased secretion of exosomes containing MICA/B.

Furthermore, the researchers demonstrated that targeting MUC1-C promotes NK cell-mediated killing of cancer cells. By interfering with the mechanisms through which MUC1-C evades NK cell recognition and destruction, the researchers were able to enhance the ability of NK cells to eliminate cancer cells.

In conclusion, this study reveals multiple mechanisms by which MUC1-C enables cancer cells to evade recognition and destruction by NK cells. These findings provide insights into the role of MUC1-C in modulating immune responses in cancer and suggest that targeting MUC1-C could be a potential therapeutic strategy to enhance NK cell-mediated killing of cancer cells.