Copy number amplification of FLAD1 promotes the progression of triple-negative breast cancer through lipid metabolism
Abstract Triple-negative breast cancer (TNBC) is known for frequent copy number alterations (CNAs) and metabolic reprogramming. However, the mechanism by which CNAs of metabolic genes drive distinct metabolic reprogramming and affect disease progression remains unclear. Through an integrated analysi...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56458-w |
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| author | Xiao-Qing Song Tian-Jian Yu Yang Ou-Yang Jia-Han Ding Yi-Zhou Jiang Zhi-Ming Shao Yi Xiao |
| author_facet | Xiao-Qing Song Tian-Jian Yu Yang Ou-Yang Jia-Han Ding Yi-Zhou Jiang Zhi-Ming Shao Yi Xiao |
| author_sort | Xiao-Qing Song |
| collection | DOAJ |
| description | Abstract Triple-negative breast cancer (TNBC) is known for frequent copy number alterations (CNAs) and metabolic reprogramming. However, the mechanism by which CNAs of metabolic genes drive distinct metabolic reprogramming and affect disease progression remains unclear. Through an integrated analysis of our TNBC multiomic dataset (n = 465) and subsequent experimental validation, we identify copy number amplification of the metabolic gene flavin-adenine dinucleotide synthetase 1 (FLAD1) as a crucial genetic event that drives TNBC progression. Mechanistically, FLAD1, but not its enzymatically inactive mutant, upregulates the enzymatic activity of FAD-dependent lysine-specific demethylase 1 (LSD1). LSD1 subsequently promotes the expression of sterol regulatory element-binding protein 1 (SREBP1) by demethylating dimethyl histone H3 lysine 9 (H3K9me2). The upregulation of SREBP1 enhances the expression of lipid biosynthesis genes, ultimately facilitating the progression of TNBC. Clinically, pharmacological inhibition of the FLAD1/LSD1/SREBP1 axis effectively suppresses FLAD1-induced tumor progression. Moreover, LSD1 inhibitor enhances the therapeutic effect of doxorubicin and sacituzumab govitecan (SG). In conclusion, our findings reveal the CNA-derived oncogenic signalling axis of FLAD1/LSD1/SREBP1 and present a promising treatment strategy for TNBC. |
| format | Article |
| id | doaj-art-96b7f31af75c4f5980c0116d2f2a24ad |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-96b7f31af75c4f5980c0116d2f2a24ad2025-02-02T12:32:47ZengNature PortfolioNature Communications2041-17232025-02-0116111710.1038/s41467-025-56458-wCopy number amplification of FLAD1 promotes the progression of triple-negative breast cancer through lipid metabolismXiao-Qing Song0Tian-Jian Yu1Yang Ou-Yang2Jia-Han Ding3Yi-Zhou Jiang4Zhi-Ming Shao5Yi Xiao6Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan UniversityKey Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan UniversityKey Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan UniversityKey Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan UniversityKey Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan UniversityKey Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan UniversityKey Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan UniversityAbstract Triple-negative breast cancer (TNBC) is known for frequent copy number alterations (CNAs) and metabolic reprogramming. However, the mechanism by which CNAs of metabolic genes drive distinct metabolic reprogramming and affect disease progression remains unclear. Through an integrated analysis of our TNBC multiomic dataset (n = 465) and subsequent experimental validation, we identify copy number amplification of the metabolic gene flavin-adenine dinucleotide synthetase 1 (FLAD1) as a crucial genetic event that drives TNBC progression. Mechanistically, FLAD1, but not its enzymatically inactive mutant, upregulates the enzymatic activity of FAD-dependent lysine-specific demethylase 1 (LSD1). LSD1 subsequently promotes the expression of sterol regulatory element-binding protein 1 (SREBP1) by demethylating dimethyl histone H3 lysine 9 (H3K9me2). The upregulation of SREBP1 enhances the expression of lipid biosynthesis genes, ultimately facilitating the progression of TNBC. Clinically, pharmacological inhibition of the FLAD1/LSD1/SREBP1 axis effectively suppresses FLAD1-induced tumor progression. Moreover, LSD1 inhibitor enhances the therapeutic effect of doxorubicin and sacituzumab govitecan (SG). In conclusion, our findings reveal the CNA-derived oncogenic signalling axis of FLAD1/LSD1/SREBP1 and present a promising treatment strategy for TNBC.https://doi.org/10.1038/s41467-025-56458-w |
| spellingShingle | Xiao-Qing Song Tian-Jian Yu Yang Ou-Yang Jia-Han Ding Yi-Zhou Jiang Zhi-Ming Shao Yi Xiao Copy number amplification of FLAD1 promotes the progression of triple-negative breast cancer through lipid metabolism Nature Communications |
| title | Copy number amplification of FLAD1 promotes the progression of triple-negative breast cancer through lipid metabolism |
| title_full | Copy number amplification of FLAD1 promotes the progression of triple-negative breast cancer through lipid metabolism |
| title_fullStr | Copy number amplification of FLAD1 promotes the progression of triple-negative breast cancer through lipid metabolism |
| title_full_unstemmed | Copy number amplification of FLAD1 promotes the progression of triple-negative breast cancer through lipid metabolism |
| title_short | Copy number amplification of FLAD1 promotes the progression of triple-negative breast cancer through lipid metabolism |
| title_sort | copy number amplification of flad1 promotes the progression of triple negative breast cancer through lipid metabolism |
| url | https://doi.org/10.1038/s41467-025-56458-w |
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