دورية أكاديمية
أعرض في EDS

Discovery of a novel hybrid coumarin-hydroxamate conjugate targeting the HDAC1-Sp1-FOSL2 signaling axis for breast cancer therapy.

التفاصيل البيبلوغرافية
العنوان: Discovery of a novel hybrid coumarin-hydroxamate conjugate targeting the HDAC1-Sp1-FOSL2 signaling axis for breast cancer therapy.
المؤلفون: Zhu S; Institute of Translational Medicine, College of Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266021, China., Zhu W; Clinical Research Center, Qingdao Municipal Hospital, Qingdao, 266071, China., Zhao K; Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Hospital), Qingdao, 266042, China., Yu J; Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Hospital), Qingdao, 266042, China., Lu W; School of Biological Science and Technology, University of Jinan, Jinan, 250022, China., Zhou R; Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai, 201306, China., Fan S; School of Biological Science and Technology, University of Jinan, Jinan, 250022, China., Kong W; Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China. 1510307407@pku.edu.cn.; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, 00250, Finland. 1510307407@pku.edu.cn.; Institute Sanqu Technology (Hangzhou) Co., Ltd., Hangzhou, China. 1510307407@pku.edu.cn., Yang F; School of Biological Science and Technology, University of Jinan, Jinan, 250022, China. bio_yangff@ujn.edu.cn., Shan P; Institute of Translational Medicine, College of Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266021, China. shanpeipei@qdu.edu.cn.
المصدر: Cell communication and signaling : CCS [Cell Commun Signal] 2024 Jul 15; Vol. 22 (1), pp. 361. Date of Electronic Publication: 2024 Jul 15.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 101170464 Publication Model: Electronic Cited Medium: Internet ISSN: 1478-811X (Electronic) Linking ISSN: 1478811X NLM ISO Abbreviation: Cell Commun Signal Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : BioMed Central, c2003-
مواضيع طبية MeSH: Coumarins*/chemistry , Coumarins*/pharmacology , Histone Deacetylase 1*/metabolism , Histone Deacetylase 1*/antagonists & inhibitors , Histone Deacetylase 1*/genetics , Breast Neoplasms*/drug therapy , Breast Neoplasms*/metabolism , Breast Neoplasms*/pathology , Breast Neoplasms*/genetics , Signal Transduction*/drug effects , Hydroxamic Acids*/pharmacology , Hydroxamic Acids*/chemistry , Hydroxamic Acids*/therapeutic use, Humans ; Female ; Animals ; Sp1 Transcription Factor/metabolism ; Mice ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylase Inhibitors/chemistry ; Cell Line, Tumor ; Molecular Docking Simulation ; Cell Proliferation/drug effects ; Mice, Nude ; Proto-Oncogene Proteins c-fos/metabolism ; Proto-Oncogene Proteins c-fos/genetics ; Mice, Inbred BALB C ; Cell Movement/drug effects ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/therapeutic use ; Drug Discovery
مستخلص: 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.
(© 2024. The Author(s).)
References: J Comput Chem. 2004 Jul 15;25(9):1157-74. (PMID: 15116359)
Dig Dis Sci. 2021 Sep;66(9):3074-3085. (PMID: 33040214)
CA Cancer J Clin. 2022 Jan;72(1):7-33. (PMID: 35020204)
J Comput Chem. 2009 Dec;30(16):2785-91. (PMID: 19399780)
J Med Chem. 2013 Jul 25;56(14):5782-96. (PMID: 23786452)
J Clin Med. 2013 Nov 22;2(4):264-82. (PMID: 26237148)
Clin Cancer Res. 2009 Jun 15;15(12):3970-7. (PMID: 19509171)
Future Oncol. 2013 Feb;9(2):255-69. (PMID: 23414475)
Cancer Lett. 2021 Nov 1;520:243-254. (PMID: 34339801)
Eur J Med Chem. 2023 Oct 5;258:115613. (PMID: 37399711)
Exp Cell Res. 2018 Dec 15;373(1-2):57-61. (PMID: 30114390)
Curr Top Med Chem. 2018;18(28):2420-2428. (PMID: 30526462)
Bioorg Chem. 2019 Oct;91:103184. (PMID: 31408831)
Br J Cancer. 2011 Jun 7;104(12):1828-35. (PMID: 21559012)
Curr Drug Targets. 2018;19(1):38-54. (PMID: 28124606)
Cancer. 2023 Nov 1;129(21):3372-3380. (PMID: 37560925)
Cancer Treat Rev. 2004 Aug;30(5):461-72. (PMID: 15245778)
Curr Med Chem. 2008;15(26):2664-79. (PMID: 18991629)
Genome Biol. 2003;4(2):206. (PMID: 12620113)
Lancet Oncol. 2018 Jul;19(7):904-915. (PMID: 29804902)
Curr Top Med Chem. 2021;21(18):1692-1709. (PMID: 33655862)
Sci Adv. 2021 Jan 8;7(2):. (PMID: 33523989)
Nature. 2000 Aug 17;406(6797):747-52. (PMID: 10963602)
Nat Protoc. 2016 May;11(5):905-19. (PMID: 27077332)
Trends Pharmacol Sci. 2018 Mar;39(3):295-306. (PMID: 29233541)
Blood. 2003 Oct 1;102(7):2615-22. (PMID: 12816865)
Int J Oncol. 2015 Jan;46(1):265-71. (PMID: 25310400)
Oncogene. 2008 May 22;27(23):3221-32. (PMID: 18071306)
Molecules. 2020 Feb 07;25(3):. (PMID: 32046013)
Mol Cell Biol. 2009 May;29(10):2483-8. (PMID: 19273606)
Future Med Chem. 2012 May;4(7):893-914. (PMID: 22571614)
J Biol Chem. 2005 Feb 4;280(5):3185-96. (PMID: 15557281)
Molecules. 2019 Jul 15;24(14):. (PMID: 31311163)
Eur J Med Chem. 2013 Feb;60:120-7. (PMID: 23287057)
Chem Commun (Camb). 2023 Apr 25;59(34):5106-5109. (PMID: 37039083)
Nat Commun. 2020 Jun 26;11(1):3252. (PMID: 32591534)
Eur J Pharm Sci. 2020 Sep 1;152:105424. (PMID: 32534193)
Mol Cell Biol. 2006 Mar;26(5):1770-85. (PMID: 16478997)
Theranostics. 2019 Oct 14;9(25):7680-7696. (PMID: 31695794)
Mol Cell. 2013 Jul 11;51(1):57-67. (PMID: 23791785)
Cancer Commun (Lond). 2022 Nov;42(11):1207-1211. (PMID: 36161715)
Breast Cancer Res Treat. 2008 Feb;107(3):337-47. (PMID: 17393299)
Genes Genomics. 2022 Jan;44(1):29-38. (PMID: 34773569)
Bioorg Med Chem. 2020 Mar 15;28(6):115345. (PMID: 32061484)
Breast. 2015 Nov;24 Suppl 2:S26-35. (PMID: 26253814)
Onco Targets Ther. 2019 Nov 05;12:9227-9237. (PMID: 31807006)
J Cell Mol Med. 2022 Jul;26(14):4048-4060. (PMID: 35748101)
Nature. 2016 Dec 22;540(7634):552-558. (PMID: 27974799)
Anticancer Res. 2014 Mar;34(3):1071-7. (PMID: 24596345)
Cell Death Dis. 2021 Mar 12;12(3):264. (PMID: 33712565)
Am J Clin Pathol. 2014 Dec;142(6):755-66. (PMID: 25389328)
Oncogene. 2002 Jan 17;21(3):427-36. (PMID: 11821955)
Cancer Res. 2021 Aug 1;81(15):4027-4040. (PMID: 33985974)
Mini Rev Med Chem. 2019;19(17):1443-1458. (PMID: 30854961)
Cancer Treat Rev. 2017 Sep;59:33-45. (PMID: 28732326)
Mol Cell Biochem. 2024 Jun;479(6):1535-1543. (PMID: 37490178)
Cancer Treat Rev. 2020 Aug;88:102033. (PMID: 32534233)
Br J Cancer. 2009 Oct 6;101(7):1044-50. (PMID: 19738609)
Future Med Chem. 2012 Mar;4(4):505-24. (PMID: 22416777)
معلومات مُعتمدة: 81903539 National Natural Science Foundation of China; 81703360 National Natural Science Foundation of China; 81803016 National Natural Science Foundation of China; ZR2022MB140 Natural Science Foundation of Shandong Province; ZR2019HB012 Natural Science Foundation of Shandong Province; 2019M650157 China Postdoctoral Science Foundation
فهرسة مساهمة: Keywords: Breast cancer; Coumarins; FOSL2; Histone deacetylases inhibitor; Metastasis; Tumor growth
المشرفين على المادة: 0 (Coumarins)
EC 3.5.1.98 (Histone Deacetylase 1)
0 (Hydroxamic Acids)
0 (Sp1 Transcription Factor)
0 (Histone Deacetylase Inhibitors)
EC 3.5.1.98 (HDAC1 protein, human)
A4VZ22K1WT (coumarin)
0 (Proto-Oncogene Proteins c-fos)
0 (Antineoplastic Agents)
تواريخ الأحداث: Date Created: 20240715 Date Completed: 20240716 Latest Revision: 20240813
رمز التحديث: 20240813
مُعرف محوري في PubMed: PMC11247895
DOI: 10.1186/s12964-024-01733-4
PMID: 39010083
قاعدة البيانات: MEDLINE
الوصف
تدمد:1478-811X
DOI:10.1186/s12964-024-01733-4