Discovery of a novel hybrid coumarin-hydroxamate conjugate targeting the HDAC1-Sp1-FOSL2 signaling axis for breast cancer therapy
Abstract Background Breast cancer is one of the most lethal cancers in women. Despite significant advances in the diagnosis and treatment of breast cancer, many patients still succumb to this disease, and thus, novel effective treatments are urgently needed. Natural product coumarin has been broadly...
| Hoofdauteurs: | , , , , , , , , , |
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| Formaat: | Artikel |
| Taal: | English |
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BMC
2024-07-01
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| Reeks: | Cell Communication and Signaling |
| Onderwerpen: | |
| Online toegang: | https://doi.org/10.1186/s12964-024-01733-4 |
| _version_ | 1827183621768740864 |
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| author | Sujie Zhu Wenjing Zhu Kaihua Zhao Jie Yu Wenxia Lu Rui Zhou Shule Fan Weikaixin Kong Feifei Yang Peipei Shan |
| author_facet | Sujie Zhu Wenjing Zhu Kaihua Zhao Jie Yu Wenxia Lu Rui Zhou Shule Fan Weikaixin Kong Feifei Yang Peipei Shan |
| author_sort | Sujie Zhu |
| collection | DOAJ |
| description | Abstract Background Breast cancer is one of the most lethal cancers in women. Despite significant advances in the diagnosis and treatment of breast cancer, many patients still succumb to this disease, and thus, novel effective treatments are urgently needed. Natural product coumarin has been broadly investigated since it reveals various biological properties in the medicinal field. Accumulating evidence indicates that histone deacetylase inhibitors (HDACIs) are promising novel anti-breast cancer agents. However, most current HDACIs exhibit only moderate effects against solid tumors and are associated with severe side effects. Thus, to develop more effective HDACIs for breast cancer therapy, hydroxamate of HDACIs was linked to coumarin core, and coumarin-hydroxamate hybrids were designed and synthesized. Methods A substituted coumarin moiety was incorporated into the classic hydroxamate HDACIs by the pharmacophore fusion strategy. ZN444B was identified by using the HDACI screening kit and cell viability assay. Molecular docking was performed to explore the binding mode of ZN444B with HDAC1. Western blot, immunofluorescent staining, cell viability, colony formation and cell migration and flow cytometry assays were used to analyze the anti-breast cancer effects of ZN444B in vitro. Orthotopic studies in mouse models were applied for preclinical evaluation of efficacy and toxicity in vivo. Proteomic analysis, dual-luciferase reporter assay, chromatin immunoprecipitation, co-immunoprecipitation, immunofluorescent staining assays along with immunohistochemical (IHC) analysis were used to elucidate the molecular basis of the actions of ZN444B. Results We synthesized and identified a novel coumarin-hydroxamate conjugate, ZN444B which possesses promising anti-breast cancer activity both in vitro and in vivo. A molecular docking model showed that ZN444B binds to HDAC1 with high affinity. Further mechanistic studies revealed that ZN444B specifically decreases FOS-like antigen 2 (FOSL2) mRNA levels by inhibiting the deacetylase activity of HDAC1 on Sp1 at K703 and abrogates the binding ability of Sp1 to the FOSL2 promoter. Furthermore, FOSL2 expression positively correlates with breast cancer progression and metastasis. Silencing FOSL2 expression decreases the sensitivity of breast cancer cells to ZN444B treatment. In addition, ZN444B shows no systemic toxicity in mice. Conclusions Our findings highlight the potential of FOSL2 as a new biomarker and therapeutic target for breast cancer and that targeting the HDAC1-Sp1-FOSL2 signaling axis with ZN444B may be a promising therapeutic strategy for breast cancer. |
| first_indexed | 2025-03-21T06:21:31Z |
| format | Article |
| id | doaj.art-79cb79b9aa9b4770b8ab2665f901b61e |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2025-03-21T06:21:31Z |
| publishDate | 2024-07-01 |
| publisher | BMC |
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| series | Cell Communication and Signaling |
| spelling | doaj.art-79cb79b9aa9b4770b8ab2665f901b61e2024-07-21T11:28:14ZengBMCCell Communication and Signaling1478-811X2024-07-0122112410.1186/s12964-024-01733-4Discovery of a novel hybrid coumarin-hydroxamate conjugate targeting the HDAC1-Sp1-FOSL2 signaling axis for breast cancer therapySujie Zhu0Wenjing Zhu1Kaihua Zhao2Jie Yu3Wenxia Lu4Rui Zhou5Shule Fan6Weikaixin Kong7Feifei Yang8Peipei Shan9Institute of Translational Medicine, College of Medicine, The Affiliated Hospital of Qingdao University, Qingdao UniversityClinical Research Center, Qingdao Municipal HospitalQingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Hospital)Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Hospital)School of Biological Science and Technology, University of JinanDepartment of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean UniversitySchool of Biological Science and Technology, University of JinanDepartment of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science CenterSchool of Biological Science and Technology, University of JinanInstitute of Translational Medicine, College of Medicine, The Affiliated Hospital of Qingdao University, Qingdao UniversityAbstract Background Breast cancer is one of the most lethal cancers in women. Despite significant advances in the diagnosis and treatment of breast cancer, many patients still succumb to this disease, and thus, novel effective treatments are urgently needed. Natural product coumarin has been broadly investigated since it reveals various biological properties in the medicinal field. Accumulating evidence indicates that histone deacetylase inhibitors (HDACIs) are promising novel anti-breast cancer agents. However, most current HDACIs exhibit only moderate effects against solid tumors and are associated with severe side effects. Thus, to develop more effective HDACIs for breast cancer therapy, hydroxamate of HDACIs was linked to coumarin core, and coumarin-hydroxamate hybrids were designed and synthesized. Methods A substituted coumarin moiety was incorporated into the classic hydroxamate HDACIs by the pharmacophore fusion strategy. ZN444B was identified by using the HDACI screening kit and cell viability assay. Molecular docking was performed to explore the binding mode of ZN444B with HDAC1. Western blot, immunofluorescent staining, cell viability, colony formation and cell migration and flow cytometry assays were used to analyze the anti-breast cancer effects of ZN444B in vitro. Orthotopic studies in mouse models were applied for preclinical evaluation of efficacy and toxicity in vivo. Proteomic analysis, dual-luciferase reporter assay, chromatin immunoprecipitation, co-immunoprecipitation, immunofluorescent staining assays along with immunohistochemical (IHC) analysis were used to elucidate the molecular basis of the actions of ZN444B. Results We synthesized and identified a novel coumarin-hydroxamate conjugate, ZN444B which possesses promising anti-breast cancer activity both in vitro and in vivo. A molecular docking model showed that ZN444B binds to HDAC1 with high affinity. Further mechanistic studies revealed that ZN444B specifically decreases FOS-like antigen 2 (FOSL2) mRNA levels by inhibiting the deacetylase activity of HDAC1 on Sp1 at K703 and abrogates the binding ability of Sp1 to the FOSL2 promoter. Furthermore, FOSL2 expression positively correlates with breast cancer progression and metastasis. Silencing FOSL2 expression decreases the sensitivity of breast cancer cells to ZN444B treatment. In addition, ZN444B shows no systemic toxicity in mice. Conclusions Our findings highlight the potential of FOSL2 as a new biomarker and therapeutic target for breast cancer and that targeting the HDAC1-Sp1-FOSL2 signaling axis with ZN444B may be a promising therapeutic strategy for breast cancer.https://doi.org/10.1186/s12964-024-01733-4Breast cancerMetastasisTumor growthHistone deacetylases inhibitorCoumarinsFOSL2 |
| spellingShingle | Sujie Zhu Wenjing Zhu Kaihua Zhao Jie Yu Wenxia Lu Rui Zhou Shule Fan Weikaixin Kong Feifei Yang Peipei Shan Discovery of a novel hybrid coumarin-hydroxamate conjugate targeting the HDAC1-Sp1-FOSL2 signaling axis for breast cancer therapy Cell Communication and Signaling Breast cancer Metastasis Tumor growth Histone deacetylases inhibitor Coumarins FOSL2 |
| title | Discovery of a novel hybrid coumarin-hydroxamate conjugate targeting the HDAC1-Sp1-FOSL2 signaling axis for breast cancer therapy |
| title_full | Discovery of a novel hybrid coumarin-hydroxamate conjugate targeting the HDAC1-Sp1-FOSL2 signaling axis for breast cancer therapy |
| title_fullStr | Discovery of a novel hybrid coumarin-hydroxamate conjugate targeting the HDAC1-Sp1-FOSL2 signaling axis for breast cancer therapy |
| title_full_unstemmed | Discovery of a novel hybrid coumarin-hydroxamate conjugate targeting the HDAC1-Sp1-FOSL2 signaling axis for breast cancer therapy |
| title_short | Discovery of a novel hybrid coumarin-hydroxamate conjugate targeting the HDAC1-Sp1-FOSL2 signaling axis for breast cancer therapy |
| title_sort | discovery of a novel hybrid coumarin hydroxamate conjugate targeting the hdac1 sp1 fosl2 signaling axis for breast cancer therapy |
| topic | Breast cancer Metastasis Tumor growth Histone deacetylases inhibitor Coumarins FOSL2 |
| url | https://doi.org/10.1186/s12964-024-01733-4 |
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