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

Sep 24, 2026

MUC1-C, a mammalian barrier-protective protein, drives oncogenesis in chronic inflammation and links to T-cell depletion and dysfunction in tumors. The study clarifies MUC1-C’s role in innate immunity by testing how targeting MUC1-C affects MICA/MICB ligands, shedding, and exosome secretion. Genetic and pharmacologic inhibition using GO-203, with promoter epigenetic analyses and exosome/NK assays, shows NK-activating ligand repression and that MUC1-C suppresses NK killing through ERp5 and RAB27A-dependent mechanisms.

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CategoryHealthcare

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Pages15

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Open access Original research MUC1-C is a master regulator of MICA/B NKG2D ligand and exosome secretion in human cancer cells Yoshihiro Morimoto,1 Nami Yamashita,1 Tatsuaki Daimon,1 Haruka Hirose,2 Shizuka Yamano,1,3 Naoki Haratake,1 Satoshi Ishikawa,1 Atrayee Bhattacharya,1 Atsushi Fushimi,1 Rehan Ahmad,1 Hidekazu Takahashi,4 Olga Dashevsky,1,3 Constantine Mitsiades,1,3 Donald Kufe 1 To cite: Morimoto Y, Yamashita N, Daimon T, et al. MUC1-C is a master regulator of MICA/B NKG2D ligand and exosome secretion in human cancer cells. Journal for ImmunoTherapy of Cancer 2023;11:e006238 . doi:10 . 1136/ jitc-2022-006238 ► Additional supplemental material is published online only. To view, please visit the journal online ([http://dx.doi.org/10](http://dx.doi.org/10) . 1136/jitc-2022-006238) . Accepted 20 January 2023 © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA 2Division of Systems Biology, Nagoya University Graduate School of Medicine Faculty of Medicine, Nagoya, Japan 3Broad Institute, Cambridge, Massachusetts, USA 4Department of Gastroenterological Surgery, Osaka University, Suita, Japan Correspondence to Dr Donald Kufe; [Donald_Kufe@dfci.harvard.edu](Donald_Kufe@dfci.harvard.edu) ABSTRACT 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. Asa 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 cellmediated killing. Conclusions These findings uncover pleotropic mechanisms by which MUC1-C confers evasion of cancer cells to NK cell recognition and destruction. BACKGROUND MUC1 evolved in mammals to protect epithelial niches from loss of homeostasis as a result of exposure to the external environment.1 2 WHAT IS ALREADY KNOWN ON THIS TOPIC | ⇒ MUC1-C suppresses anticancer cytotoxic T lymphocyte functions; however, there is no known involvement of MUC1-C in regulating innate immunity.
WHAT THIS STUDY ADDS | | --- | | ⇒ Our results demonstrate that MUC1-C regulates MHC class I chain-related polypeptide A/B expression, shedding and secretion on exosomes in association with suppression of natural killer (NK) cell kil

FAQs

What is the central question of the study?

Whether MUC1-C regulates natural killer (NK) cell function by controlling MICA/MICB ligands and their presentation through exosome secretion.

How did the researchers assess the role of MUC1-C?

They targeted MUC1-C genetically and with the GO-203 inhibitor, measured MICA/B expression and shedding, analyzed promoter H3K27 and DNA methylation, studied MUC1-C interactions with ERp5 and RAB27A, and tested NK cell-mediated killing.

What did MUC1-C targeting change in cancer cells and NK cells?

Targeting MUC1-C increased intracellular and cell-surface MICA/B but inhibited exosome secretion carrying MICA/B, and it promoted NK-cell mediated killing of cancer targets.

Sep 24, 2026

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