Saikosaponin D Mitigates Radioresistance in Triple-Negative Breast Cancer by Inducing MRE11 De-Lactylation via HIF1α/HDAC5 Pathway.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος:	Saikosaponin D Mitigates Radioresistance in Triple-Negative Breast Cancer by Inducing MRE11 De-Lactylation via HIF1α/HDAC5 Pathway.
Συγγραφείς:	Li J; Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, China.; Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang, China., Feng L; School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China., Zhang L; Department of Radiation Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China., Zhang W; Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, China., Zhang Y; School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China., Liu X; School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China., Cai Q; Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, China., Zhao W; Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang, China., Huang G; Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, China., Lu C; Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, China.; School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China.
Πηγή:	Theranostics [Theranostics] 2025 Aug 11; Vol. 15 (17), pp. 8935-8951. Date of Electronic Publication: 2025 Aug 11 (Print Publication: 2025).
Τύπος έκδοσης:	Journal Article
Γλώσσα:	English
Στοιχεία περιοδικού:	Publisher: Ivyspring International Publisher Country of Publication: Australia NLM ID: 101552395 Publication Model: eCollection Cited Medium: Internet ISSN: 1838-7640 (Electronic) Linking ISSN: 18387640 NLM ISO Abbreviation: Theranostics Subsets: MEDLINE
Imprint Name(s):	Original Publication: Wyoming, N.S.W. : Ivyspring International Publisher, 2011-
Ιατρικοί όροι (MeSH):	Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/radiotherapy , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/genetics , Saponins/pharmacology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Radiation Tolerance/drug effects , Histone Deacetylases/metabolism , Histone Deacetylases/genetics , Oleanolic Acid/analogs & derivatives , Oleanolic Acid/pharmacology , MRE11 Homologue Protein/metabolism , MRE11 Homologue Protein/genetics , Radiation-Sensitizing Agents*/pharmacology, Signal Transduction/drug effects ; DNA Repair/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Cell Line, Tumor ; Female ; Animals ; Mice
Περίληψη:	Background: Triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype, exhibits poor prognosis due to radiotherapy resistance. However, the underlying mechanisms and effective therapeutic agents remain elusive. Methods: We employed lactate/oxamate to assess DNA damage/repair in irradiated TNBC cell lines. Lentiviral vectors for MRE11/HDAC5 constructs and shRNA were used to explore lactylation via Western blot/Co-IP. TCGA data mining, tissue microarrays, proteomics-MS, and gene expression profiling were used to dissect Saikosaponin D (SSD)'s radiosensitizing mechanisms. Promoter luciferase assays and ChIP-qPCR were performed to map SSD-induced HIF1α binding sites on the HDAC5 promoter. Results: Elevated endogenous lactate in radioresistant TNBC cells promoted DNA repair via MRE11 Lys⁶⁷³ lactylation, a critical modification conferring radioresistance. HDAC5 was identified as the key delactylase for MRE11 Lys^673, validated by HADDOCK docking (hydrogen bond between MRE11 Lys⁶⁷³ and HDAC5 Ser¹⁸) and Co-IP (HDAC5 overexpression reduced K⁶⁷³ lactylation). TCGA and clinical tissue microarrays confirmed HDAC5 downregulation in TNBC. SSD inhibits the malignant phenotype of TNBC and enhances radiotherapy efficacy by inhibition on MRE11 lactylation via upregulating HDAC5. Mechanistically, SSD upregulated HIF1α to bind the HDAC5 promoter (-342bp to -20bp region) to activate its expression. Conclusion: Lactate-driven MRE11 Lys⁶⁷³ lactylation mediates radioresistance, while SSD reverses this via HIF1α/HDAC5 axis activation. Our findings identify SSD as a radiosensitizer and HDAC5/MRE11 as potential therapeutic targets for TNBC. (© The author(s).)
Competing Interests:	Competing Interests: The authors have declared that no competing interest exists.
References:	Nat Metab. 2021 Feb;3(2):182-195. (PMID: 33619381) Cell. 2011 Mar 4;144(5):646-74. (PMID: 21376230) Cancer Lett. 2015 Nov 28;368(2):156-63. (PMID: 25911239) Br J Cancer. 2020 Aug;123(4):633-643. (PMID: 32488136) Nucleic Acids Res. 2024 Jan 5;52(D1):D368-D375. (PMID: 37933859) Cell Signal. 2024 Dec;124:111468. (PMID: 39395526) Nat Rev Mol Cell Biol. 2019 Nov;20(11):698-714. (PMID: 31263220) Front Pharmacol. 2022 Jun 02;13:926802. (PMID: 35721121) Genome Biol. 2021 Mar 16;22(1):85. (PMID: 33726814) Hepatology. 2023 Dec 1;78(6):1800-1815. (PMID: 36651176) Cancer Immunol Res. 2020 Nov;8(11):1440-1451. (PMID: 32917658) J Biochem. 2020 Apr 1;167(4):365-370. (PMID: 31742336) Nature. 2021 Mar;591(7851):645-651. (PMID: 33589820) Clin Cancer Res. 2008 Nov 1;14(21):6744-50. (PMID: 18980967) Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):20605-10. (PMID: 24297933) J Hematol Oncol. 2022 Aug 29;15(1):121. (PMID: 36038913) Cell. 2019 Jan 24;176(3):505-519.e22. (PMID: 30612738) Sci Adv. 2022 Jan 21;8(3):eabi6696. (PMID: 35044827) Nature. 2024 Jul;631(8021):663-669. (PMID: 38961290) Proc Natl Acad Sci U S A. 2020 Dec 1;117(48):30628-30638. (PMID: 33199625) Cell Oncol (Dordr). 2023 Jun;46(3):465-480. (PMID: 36656507) Cell. 2017 Feb 9;168(4):644-656. (PMID: 28187286) Nature. 2021 Aug;596(7873):583-589. (PMID: 34265844) Oncol Rep. 2020 Oct;44(4):1355-1364. (PMID: 32945483) Cancer Lett. 2021 Aug 28;514:1-11. (PMID: 34022282) Biomed Pharmacother. 2018 Dec;108:724-733. (PMID: 30248540) iScience. 2024 Sep 10;27(10):110911. (PMID: 39351192) Mol Cell. 2022 May 5;82(9):1660-1677.e10. (PMID: 35320754) Adv Sci (Weinh). 2023 Feb;10(5):e2203884. (PMID: 36563124) Biomolecules. 2022 Nov 27;12(12):. (PMID: 36551192) Nat Commun. 2023 Oct 20;14(1):6523. (PMID: 37863889) Mol Cancer. 2024 May 6;23(1):90. (PMID: 38711083) Nat Commun. 2020 May 22;11(1):2578. (PMID: 32444598) Cell. 2008 Oct 3;135(1):85-96. (PMID: 18854157) Nucleic Acids Res. 2015 Sep 30;43(17):8352-67. (PMID: 26240375) J Exp Clin Cancer Res. 2023 Oct 28;42(1):285. (PMID: 37891669) Clin Transl Med. 2020 Dec;10(8):e233. (PMID: 33377659) J Exp Clin Cancer Res. 2022 Oct 14;41(1):303. (PMID: 36242053) Cell. 2024 Jan 18;187(2):294-311.e21. (PMID: 38128537) Cell Commun Signal. 2015 Jul 25;13:36. (PMID: 26208712) Cancer Res. 2021 Mar 15;81(6):1486-1499. (PMID: 33419772) Nature. 2019 Oct;574(7779):575-580. (PMID: 31645732) Nat Rev Gastroenterol Hepatol. 2020 May;17(5):298-313. (PMID: 32005946) Nat Protoc. 2024 Nov;19(11):3219-3241. (PMID: 38886530) Cell Death Differ. 2022 Jan;29(1):133-146. (PMID: 34363018) Protein Cell. 2022 Dec;13(12):877-919. (PMID: 34050894) Int J Radiat Biol. 2019 Jul;95(7):912-919. (PMID: 30822194) Circ Res. 2022 Nov 11;131(11):893-908. (PMID: 36268709) Cancer Res. 2002 May 15;62(10):2913-22. (PMID: 12019172) BMJ. 2023 May 30;381:e071674. (PMID: 37253507)
Contributed Indexing:	Keywords: Lactylation; Saikosaponin D (SSD); Triple-negative breast cancer (TNBC); histone deacetylase (HDAC) 5; radioresistance
Substance Nomenclature:	0 (Saponins) 0 (Hypoxia-Inducible Factor 1, alpha Subunit) 0 (HIF1A protein, human) EC 3.5.1.98 (Histone Deacetylases) 6SMK8R7TGJ (Oleanolic Acid) EC 3.5.1.98 (HDAC5 protein, human) EC 3.1.- (MRE11 Homologue Protein) 0 (Radiation-Sensitizing Agents)
Entry Date(s):	Date Created: 20250918 Date Completed: 20250918 Latest Revision: 20250920
Update Code:	20260130
PubMed Central ID:	PMC12439262
DOI:	10.7150/thno.113517
PMID:	40963916
Βάση Δεδομένων:	MEDLINE

Full Text Finder

Περιγραφή
ISSN:	1838-7640
DOI:	10.7150/thno.113517