Diabetes is causally associated with increased breast cancer mortality by inducing FIBCD1 to activate MCM5-mediated cell cycle arrest via modulating H3K27ac
Abstract Breast cancer (BC) is the most common tumor worldwide and it has been recognized that up to one third of BC patients have co-existing diabetes mellitus (DM) (BC-DM). Although many observational studies have indicated an association between DM and BC, the causal relationship of DM and BC pro...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07849-w |
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| author | Binbin Tan Yang Liu Qianqian Chen Weijie Yang Wenhan Yang Kaiping Gao Li Fu Tiantian Zhang Penglong Chen Yongyi Huang Yuting Wang Guoqiang Zhang Juan Xiong Rihong Zhai |
| author_facet | Binbin Tan Yang Liu Qianqian Chen Weijie Yang Wenhan Yang Kaiping Gao Li Fu Tiantian Zhang Penglong Chen Yongyi Huang Yuting Wang Guoqiang Zhang Juan Xiong Rihong Zhai |
| author_sort | Binbin Tan |
| collection | DOAJ |
| description | Abstract Breast cancer (BC) is the most common tumor worldwide and it has been recognized that up to one third of BC patients have co-existing diabetes mellitus (DM) (BC-DM). Although many observational studies have indicated an association between DM and BC, the causal relationship of DM and BC prognosis remained uncertain and the molecular mechanisms underlying BC-DM are largely unclear. In this study, we used causal inference methods, including g-computation (GC), inverse probability of treatment weighting (IPTW), targeted maximum likelihood estimation (TMLE), and TMLE-super learner (TMLE-SL), to comprehensively analyze the association of DM with BC mortality in a cohort of 3386 BC patients. We found that the adjusted odds ratios (OR) and 95% confidence intervals (95% CI) for 5-year mortality in BC-DM patients were 1.926 (1.082, 2.943), 2.268 (1.063, 3.974), 1.917 (1.091, 2.953), and 2.113 (1.365, 3.270), respectively. Further transcriptomic and qPCR analyses identified that FIBCD1 was highly expressed in BC-DM tumor tissues and in BC cells under hyperglycemia conditions. Functionally, upregulation of FIBCD1 promoted proliferation, migration, and invasion capacities of BC cells in a glucose level-dependent manner. While knockdown of FIBCD1 suppressed BC tumor growth in diabetic mice. Integrated RNA-seq and Ribo-seq analysis revealed that MCM5 was a target of FIBCD1. Mechanistically, hyperglycemia-activated FIBCD1 promoted MCM5 expression to induce S-phase cell cycle arrest by upregulating histone H3K27ac levels in MCM5 promoter via the PDH-acetyl-CoA axis. Our findings provide new evidence that co-existing DM has a causal effect on overall mortality in BC-DM patients. Targeting FIBCD1 may be a promising therapy for BC-DM. |
| format | Article |
| id | doaj-art-ca7ec2a0ee7544d697367c8ea167b0b0 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-ca7ec2a0ee7544d697367c8ea167b0b02025-08-20T03:42:10ZengNature Publishing GroupCell Death and Disease2041-48892025-07-0116111610.1038/s41419-025-07849-wDiabetes is causally associated with increased breast cancer mortality by inducing FIBCD1 to activate MCM5-mediated cell cycle arrest via modulating H3K27acBinbin Tan0Yang Liu1Qianqian Chen2Weijie Yang3Wenhan Yang4Kaiping Gao5Li Fu6Tiantian Zhang7Penglong Chen8Yongyi Huang9Yuting Wang10Guoqiang Zhang11Juan Xiong12Rihong Zhai13Department of Pharmacology and International Cancer Center, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University Medical SchoolDepartment of Surgery, Harbin Medical University Cancer HospitalCancer Centre, Faculty of Health Sciences, University of MacauDepartment of Pharmacology and International Cancer Center, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University Medical SchoolNational Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, Southern University of Science and TechnologySchool of Public Health, Guangdong Key Laboratory for Genome Stability & Disease Prevention, Shenzhen University Medical SchoolDepartment of Pharmacology and International Cancer Center, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University Medical SchoolDepartment of Pharmacology and International Cancer Center, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University Medical SchoolDepartment of Pharmacology and International Cancer Center, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University Medical SchoolSchool of Public Health, Guangdong Key Laboratory for Genome Stability & Disease Prevention, Shenzhen University Medical SchoolSchool of Public Health, Guangdong Key Laboratory for Genome Stability & Disease Prevention, Shenzhen University Medical SchoolDepartment of Surgery, Harbin Medical University Cancer HospitalSchool of Public Health, Guangdong Key Laboratory for Genome Stability & Disease Prevention, Shenzhen University Medical SchoolDepartment of Pharmacology and International Cancer Center, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University Medical SchoolAbstract Breast cancer (BC) is the most common tumor worldwide and it has been recognized that up to one third of BC patients have co-existing diabetes mellitus (DM) (BC-DM). Although many observational studies have indicated an association between DM and BC, the causal relationship of DM and BC prognosis remained uncertain and the molecular mechanisms underlying BC-DM are largely unclear. In this study, we used causal inference methods, including g-computation (GC), inverse probability of treatment weighting (IPTW), targeted maximum likelihood estimation (TMLE), and TMLE-super learner (TMLE-SL), to comprehensively analyze the association of DM with BC mortality in a cohort of 3386 BC patients. We found that the adjusted odds ratios (OR) and 95% confidence intervals (95% CI) for 5-year mortality in BC-DM patients were 1.926 (1.082, 2.943), 2.268 (1.063, 3.974), 1.917 (1.091, 2.953), and 2.113 (1.365, 3.270), respectively. Further transcriptomic and qPCR analyses identified that FIBCD1 was highly expressed in BC-DM tumor tissues and in BC cells under hyperglycemia conditions. Functionally, upregulation of FIBCD1 promoted proliferation, migration, and invasion capacities of BC cells in a glucose level-dependent manner. While knockdown of FIBCD1 suppressed BC tumor growth in diabetic mice. Integrated RNA-seq and Ribo-seq analysis revealed that MCM5 was a target of FIBCD1. Mechanistically, hyperglycemia-activated FIBCD1 promoted MCM5 expression to induce S-phase cell cycle arrest by upregulating histone H3K27ac levels in MCM5 promoter via the PDH-acetyl-CoA axis. Our findings provide new evidence that co-existing DM has a causal effect on overall mortality in BC-DM patients. Targeting FIBCD1 may be a promising therapy for BC-DM.https://doi.org/10.1038/s41419-025-07849-w |
| spellingShingle | Binbin Tan Yang Liu Qianqian Chen Weijie Yang Wenhan Yang Kaiping Gao Li Fu Tiantian Zhang Penglong Chen Yongyi Huang Yuting Wang Guoqiang Zhang Juan Xiong Rihong Zhai Diabetes is causally associated with increased breast cancer mortality by inducing FIBCD1 to activate MCM5-mediated cell cycle arrest via modulating H3K27ac Cell Death and Disease |
| title | Diabetes is causally associated with increased breast cancer mortality by inducing FIBCD1 to activate MCM5-mediated cell cycle arrest via modulating H3K27ac |
| title_full | Diabetes is causally associated with increased breast cancer mortality by inducing FIBCD1 to activate MCM5-mediated cell cycle arrest via modulating H3K27ac |
| title_fullStr | Diabetes is causally associated with increased breast cancer mortality by inducing FIBCD1 to activate MCM5-mediated cell cycle arrest via modulating H3K27ac |
| title_full_unstemmed | Diabetes is causally associated with increased breast cancer mortality by inducing FIBCD1 to activate MCM5-mediated cell cycle arrest via modulating H3K27ac |
| title_short | Diabetes is causally associated with increased breast cancer mortality by inducing FIBCD1 to activate MCM5-mediated cell cycle arrest via modulating H3K27ac |
| title_sort | diabetes is causally associated with increased breast cancer mortality by inducing fibcd1 to activate mcm5 mediated cell cycle arrest via modulating h3k27ac |
| url | https://doi.org/10.1038/s41419-025-07849-w |
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