Respiratory complex I‐mediated NAD+ regeneration regulates cancer cell proliferation through the transcriptional and translational control of p21Cip1 expression by SIRT3 and SIRT7
The role of the electron transport chain (ETC) in cell proliferation control beyond its crucial function in supporting ATP generation has recently emerged. In this study, we found that, among the four ETC complexes, the complex I (CI)‐mediated NAD+ regeneration is important for cancer cell prolifera...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2025-06-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13808 |
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| author | Masato Higurashi Kazunori Mori Hidetsugu Nakagawa Momoko Uchida Fumihiro Ishikawa Motoko Shibanuma |
| author_facet | Masato Higurashi Kazunori Mori Hidetsugu Nakagawa Momoko Uchida Fumihiro Ishikawa Motoko Shibanuma |
| author_sort | Masato Higurashi |
| collection | DOAJ |
| description | The role of the electron transport chain (ETC) in cell proliferation control beyond its crucial function in supporting ATP generation has recently emerged. In this study, we found that, among the four ETC complexes, the complex I (CI)‐mediated NAD+ regeneration is important for cancer cell proliferation. In cancer cells, a decrease in CI activity by RNA interference (RNAi) against NADH:ubiquinone oxidoreductase core subunit V1 (NDUFV1) arrested the cell cycle at the G1/S phase, accompanying upregulation of p21Cip1 cyclin‐dependent kinase inhibitor expression. Mechanistically, a decrease in the NAD+/NADH ratio downregulated SIRT3 and SIRT7 function, which suppressed p21Cip1 expression at the translational and transcriptional levels, respectively, resulting in the upregulation of the antiproliferative molecule. Importantly, high expression levels of the core subunits of CI correlated with poor prognosis in patients with the hormone receptor(+)/human epidermal growth factor receptor 2(−) (HR+/HER2−) subtype of breast cancer. Therefore, NDUFV1 and SIRT3/7 have emerged as promising therapeutic targets against this breast cancer subtype. |
| format | Article |
| id | doaj-art-c85e4e0dad6d47b9a8480c2369e8dc15 |
| institution | Kabale University |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-c85e4e0dad6d47b9a8480c2369e8dc152025-08-20T03:44:52ZengWileyMolecular Oncology1574-78911878-02612025-06-011961775179610.1002/1878-0261.13808Respiratory complex I‐mediated NAD+ regeneration regulates cancer cell proliferation through the transcriptional and translational control of p21Cip1 expression by SIRT3 and SIRT7Masato Higurashi0Kazunori Mori1Hidetsugu Nakagawa2Momoko Uchida3Fumihiro Ishikawa4Motoko Shibanuma5Division of Cancer Cell Biology, Department of Pharmaceutical Sciences Showa University Graduate School of Pharmacy Tokyo JapanDivision of Cancer Cell Biology, Department of Pharmaceutical Sciences Showa University Graduate School of Pharmacy Tokyo JapanDivision of Cancer Cell Biology, Department of Pharmaceutical Sciences Showa University Graduate School of Pharmacy Tokyo JapanDivision of Cancer Cell Biology, Department of Pharmaceutical Sciences Showa University Graduate School of Pharmacy Tokyo JapanCenter for Biotechnology Showa University Tokyo JapanDivision of Cancer Cell Biology, Department of Pharmaceutical Sciences Showa University Graduate School of Pharmacy Tokyo JapanThe role of the electron transport chain (ETC) in cell proliferation control beyond its crucial function in supporting ATP generation has recently emerged. In this study, we found that, among the four ETC complexes, the complex I (CI)‐mediated NAD+ regeneration is important for cancer cell proliferation. In cancer cells, a decrease in CI activity by RNA interference (RNAi) against NADH:ubiquinone oxidoreductase core subunit V1 (NDUFV1) arrested the cell cycle at the G1/S phase, accompanying upregulation of p21Cip1 cyclin‐dependent kinase inhibitor expression. Mechanistically, a decrease in the NAD+/NADH ratio downregulated SIRT3 and SIRT7 function, which suppressed p21Cip1 expression at the translational and transcriptional levels, respectively, resulting in the upregulation of the antiproliferative molecule. Importantly, high expression levels of the core subunits of CI correlated with poor prognosis in patients with the hormone receptor(+)/human epidermal growth factor receptor 2(−) (HR+/HER2−) subtype of breast cancer. Therefore, NDUFV1 and SIRT3/7 have emerged as promising therapeutic targets against this breast cancer subtype.https://doi.org/10.1002/1878-0261.13808breast cancerNAD+p21Cip1respiratory complex ISIRT |
| spellingShingle | Masato Higurashi Kazunori Mori Hidetsugu Nakagawa Momoko Uchida Fumihiro Ishikawa Motoko Shibanuma Respiratory complex I‐mediated NAD+ regeneration regulates cancer cell proliferation through the transcriptional and translational control of p21Cip1 expression by SIRT3 and SIRT7 Molecular Oncology breast cancer NAD+ p21Cip1 respiratory complex I SIRT |
| title | Respiratory complex I‐mediated NAD+ regeneration regulates cancer cell proliferation through the transcriptional and translational control of p21Cip1 expression by SIRT3 and SIRT7 |
| title_full | Respiratory complex I‐mediated NAD+ regeneration regulates cancer cell proliferation through the transcriptional and translational control of p21Cip1 expression by SIRT3 and SIRT7 |
| title_fullStr | Respiratory complex I‐mediated NAD+ regeneration regulates cancer cell proliferation through the transcriptional and translational control of p21Cip1 expression by SIRT3 and SIRT7 |
| title_full_unstemmed | Respiratory complex I‐mediated NAD+ regeneration regulates cancer cell proliferation through the transcriptional and translational control of p21Cip1 expression by SIRT3 and SIRT7 |
| title_short | Respiratory complex I‐mediated NAD+ regeneration regulates cancer cell proliferation through the transcriptional and translational control of p21Cip1 expression by SIRT3 and SIRT7 |
| title_sort | respiratory complex i mediated nad regeneration regulates cancer cell proliferation through the transcriptional and translational control of p21cip1 expression by sirt3 and sirt7 |
| topic | breast cancer NAD+ p21Cip1 respiratory complex I SIRT |
| url | https://doi.org/10.1002/1878-0261.13808 |
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