MUC1-C is a master regulator of MICA/B NKG2D ligand and exosome secretion in human cancer cells
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 microenvi...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-02-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/2/e006238.full |
| _version_ | 1828014669503135744 |
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| author | Satoshi Ishikawa Donald Kufe Constantine Mitsiades Nami Yamashita Atsushi Fushimi Atrayee Bhattacharya Yoshihiro Morimoto Tatsuaki Daimon Haruka Hirose Shizuka Yamano Naoki Haratake Rehan Ahmad Hidekazu Takahashi Olga Dashevsky |
| author_facet | Satoshi Ishikawa Donald Kufe Constantine Mitsiades Nami Yamashita Atsushi Fushimi Atrayee Bhattacharya Yoshihiro Morimoto Tatsuaki Daimon Haruka Hirose Shizuka Yamano Naoki Haratake Rehan Ahmad Hidekazu Takahashi Olga Dashevsky |
| author_sort | Satoshi Ishikawa |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T10:04:25Z |
| format | Article |
| id | doaj.art-4da912c6510f4d72bcbe786c63f92cda |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-10T10:04:25Z |
| publishDate | 2023-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-4da912c6510f4d72bcbe786c63f92cda2023-02-16T02:30:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-02-0111210.1136/jitc-2022-006238MUC1-C is a master regulator of MICA/B NKG2D ligand and exosome secretion in human cancer cellsSatoshi Ishikawa0Donald Kufe1Constantine Mitsiades2Nami Yamashita3Atsushi Fushimi4Atrayee Bhattacharya5Yoshihiro Morimoto6Tatsuaki Daimon7Haruka Hirose8Shizuka Yamano9Naoki Haratake10Rehan Ahmad11Hidekazu Takahashi12Olga Dashevsky13Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADivision of Systems Biology, Nagoya University Graduate School of Medicine Faculty of Medicine, Nagoya, JapanDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Gastroenterological Surgery, Osaka University, Suita, JapanDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USABackground 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.https://jitc.bmj.com/content/11/2/e006238.full |
| spellingShingle | Satoshi Ishikawa Donald Kufe Constantine Mitsiades Nami Yamashita Atsushi Fushimi Atrayee Bhattacharya Yoshihiro Morimoto Tatsuaki Daimon Haruka Hirose Shizuka Yamano Naoki Haratake Rehan Ahmad Hidekazu Takahashi Olga Dashevsky MUC1-C is a master regulator of MICA/B NKG2D ligand and exosome secretion in human cancer cells Journal for ImmunoTherapy of Cancer |
| title | MUC1-C is a master regulator of MICA/B NKG2D ligand and exosome secretion in human cancer cells |
| title_full | MUC1-C is a master regulator of MICA/B NKG2D ligand and exosome secretion in human cancer cells |
| title_fullStr | MUC1-C is a master regulator of MICA/B NKG2D ligand and exosome secretion in human cancer cells |
| title_full_unstemmed | MUC1-C is a master regulator of MICA/B NKG2D ligand and exosome secretion in human cancer cells |
| title_short | MUC1-C is a master regulator of MICA/B NKG2D ligand and exosome secretion in human cancer cells |
| title_sort | muc1 c is a master regulator of mica b nkg2d ligand and exosome secretion in human cancer cells |
| url | https://jitc.bmj.com/content/11/2/e006238.full |
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