PHB2 promotes colorectal cancer cell proliferation and tumorigenesis through NDUFS1-mediated oxidative phosphorylation
Abstract The alteration of cellular energy metabolism is a hallmark of colorectal cancer (CRC). Accumulating evidence has suggested oxidative phosphorylation (OXPHOS) is upregulated to meet the demand for energy in tumor initiation and development. However, the role of OXPHOS and its regulatory mech...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05575-9 |
| _version_ | 1828056659704938496 |
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| author | Lin Ren Li Meng Jing Gao Mingdian Lu Chengyu Guo Yunyun Li Ziye Rong Yan Ye |
| author_facet | Lin Ren Li Meng Jing Gao Mingdian Lu Chengyu Guo Yunyun Li Ziye Rong Yan Ye |
| author_sort | Lin Ren |
| collection | DOAJ |
| description | Abstract The alteration of cellular energy metabolism is a hallmark of colorectal cancer (CRC). Accumulating evidence has suggested oxidative phosphorylation (OXPHOS) is upregulated to meet the demand for energy in tumor initiation and development. However, the role of OXPHOS and its regulatory mechanism in CRC tumorigenesis and progression remain unclear. Here, we reveal that Prohibitin 2 (PHB2) expression is elevated in precancerous adenomas and CRC, which promotes cell proliferation and tumorigenesis of CRC. Additionally, knockdown of PHB2 significantly reduces mitochondrial OXPHOS levels in CRC cells. Meanwhile, NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1), as a PHB2 binding partner, is screened and identified by co-immunoprecipitation and mass spectrometry. Furthermore, PHB2 directly interacts with NDUFS1 and they co-localize in mitochondria, which facilitates NDUFS1 binding to NADH:ubiquinone oxidoreductase core subunit V1 (NDUFV1), regulating the activity of complex I. Consistently, partial inhibition of complex I activity also abrogates the increased cell proliferation induced by overexpression of PHB2 in normal human intestinal epithelial cells and CRC cells. Collectively, these results indicate that increased PHB2 directly interacts with NDUFS1 to stabilize mitochondrial complex I and enhance its activity, leading to upregulated OXPHOS levels, thereby promoting cell proliferation and tumorigenesis of CRC. Our findings provide a new perspective for understanding CRC energy metabolism, as well as novel intervention strategies for CRC therapeutics. |
| first_indexed | 2024-04-10T20:59:05Z |
| format | Article |
| id | doaj.art-a3d62021a0c243e8928c5976c6a94a2a |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-10T20:59:05Z |
| publishDate | 2023-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-a3d62021a0c243e8928c5976c6a94a2a2023-01-22T12:26:47ZengNature Publishing GroupCell Death and Disease2041-48892023-01-0114111110.1038/s41419-023-05575-9PHB2 promotes colorectal cancer cell proliferation and tumorigenesis through NDUFS1-mediated oxidative phosphorylationLin Ren0Li Meng1Jing Gao2Mingdian Lu3Chengyu Guo4Yunyun Li5Ziye Rong6Yan Ye7Department of Immunology, School of Basic Medical Sciences, Anhui Medical UniversityDepartment of Immunology, School of Basic Medical Sciences, Anhui Medical UniversityDepartment of Immunology, School of Basic Medical Sciences, Anhui Medical UniversityDepartment of General Surgery, The First Affiliated Hospital of Anhui Medical UniversityDepartment of Immunology, School of Basic Medical Sciences, Anhui Medical UniversityDepartment of Immunology, School of Basic Medical Sciences, Anhui Medical UniversityDepartment of Immunology, School of Basic Medical Sciences, Anhui Medical UniversityDepartment of Immunology, School of Basic Medical Sciences, Anhui Medical UniversityAbstract The alteration of cellular energy metabolism is a hallmark of colorectal cancer (CRC). Accumulating evidence has suggested oxidative phosphorylation (OXPHOS) is upregulated to meet the demand for energy in tumor initiation and development. However, the role of OXPHOS and its regulatory mechanism in CRC tumorigenesis and progression remain unclear. Here, we reveal that Prohibitin 2 (PHB2) expression is elevated in precancerous adenomas and CRC, which promotes cell proliferation and tumorigenesis of CRC. Additionally, knockdown of PHB2 significantly reduces mitochondrial OXPHOS levels in CRC cells. Meanwhile, NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1), as a PHB2 binding partner, is screened and identified by co-immunoprecipitation and mass spectrometry. Furthermore, PHB2 directly interacts with NDUFS1 and they co-localize in mitochondria, which facilitates NDUFS1 binding to NADH:ubiquinone oxidoreductase core subunit V1 (NDUFV1), regulating the activity of complex I. Consistently, partial inhibition of complex I activity also abrogates the increased cell proliferation induced by overexpression of PHB2 in normal human intestinal epithelial cells and CRC cells. Collectively, these results indicate that increased PHB2 directly interacts with NDUFS1 to stabilize mitochondrial complex I and enhance its activity, leading to upregulated OXPHOS levels, thereby promoting cell proliferation and tumorigenesis of CRC. Our findings provide a new perspective for understanding CRC energy metabolism, as well as novel intervention strategies for CRC therapeutics.https://doi.org/10.1038/s41419-023-05575-9 |
| spellingShingle | Lin Ren Li Meng Jing Gao Mingdian Lu Chengyu Guo Yunyun Li Ziye Rong Yan Ye PHB2 promotes colorectal cancer cell proliferation and tumorigenesis through NDUFS1-mediated oxidative phosphorylation Cell Death and Disease |
| title | PHB2 promotes colorectal cancer cell proliferation and tumorigenesis through NDUFS1-mediated oxidative phosphorylation |
| title_full | PHB2 promotes colorectal cancer cell proliferation and tumorigenesis through NDUFS1-mediated oxidative phosphorylation |
| title_fullStr | PHB2 promotes colorectal cancer cell proliferation and tumorigenesis through NDUFS1-mediated oxidative phosphorylation |
| title_full_unstemmed | PHB2 promotes colorectal cancer cell proliferation and tumorigenesis through NDUFS1-mediated oxidative phosphorylation |
| title_short | PHB2 promotes colorectal cancer cell proliferation and tumorigenesis through NDUFS1-mediated oxidative phosphorylation |
| title_sort | phb2 promotes colorectal cancer cell proliferation and tumorigenesis through ndufs1 mediated oxidative phosphorylation |
| url | https://doi.org/10.1038/s41419-023-05575-9 |
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