HDAC1 and FOXK1 mediate EGFR-TKI resistance of non-small cell lung cancer through miR-33a silencing.

Publisher: BioMed Central Country of Publication: England NLM ID: 101190741 Publication Model: Electronic Cited Medium: Internet ISSN: 1479-5876 (Electronic) Linking ISSN: 14795876 NLM ISO Abbreviation: J Transl Med Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2003-

Carcinoma, Non-Small-Cell Lung*/genetics ; Carcinoma, Non-Small-Cell Lung*/pathology ; Carcinoma, Non-Small-Cell Lung*/drug therapy ; Drug Resistance, Neoplasm*/genetics ; Drug Resistance, Neoplasm*/drug effects ; ErbB Receptors*/metabolism ; Forkhead Transcription Factors*/metabolism ; Forkhead Transcription Factors*/genetics ; Gene Silencing* ; Histone Deacetylase 1*/metabolism ; Histone Deacetylase 1*/genetics ; Lung Neoplasms*/genetics ; Lung Neoplasms*/pathology ; Lung Neoplasms*/drug therapy ; MicroRNAs*/genetics ; MicroRNAs*/metabolism ; Protein Kinase Inhibitors*/pharmacology ; Protein Kinase Inhibitors*/therapeutic use; Animals ; Humans ; Mice ; Apoptosis/drug effects ; Apoptosis/genetics ; Base Sequence ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Movement/genetics ; Cell Proliferation/drug effects ; Gefitinib/pharmacology ; Gefitinib/therapeutic use ; Gene Expression Regulation, Neoplastic/drug effects ; Mice, Inbred BALB C ; Mice, Nude

Background: The development of acquired EGFR-TKI treatment resistance is still a major clinical challenge in the treatment of non-small cell lung cancer (NSCLC). This study aimed to investigate the role of HDAC1/FOXK1/miR-33a signaling in EGFR-TKI resistance.
Methods: The expression levels of miR-33a, HDAC1, and FOXK1 were examined using quantitative polymerase chain reaction (PCR) and bioinformatics analysis. Cell proliferation, migration, and apoptosis were explored by cell number assay, Transwell, and flow cytometry assays, respectively. After overexpression or knockdown of HDAC1, miR-33a expression in the cells, cell functions were tested. Immunoprecipitation and correlation analyses were used to evaluate the interaction between HDAC1 and FOXK1 protein. The tumor-suppressive role of miR-33a was investigated by animal experiments.
Results: The suppression of miR-33a increased TKI resistance by affecting cell proliferation, migration, and apoptosis in gefitinib-resistant cells. HDAC1 is the key upstream molecule that inhibits miR-33 expression. HDAC1 upregulation increased gefitinib resistance by its binding to FOXK1 in cells to silence miR-33a expression. MiR-33a overexpression exerts tumor-suppressive effects by negatively regulating ABCB7 and p70S6K1 expression. Moreover, overexpression of miR-33a inhibited tumor growth in a xenograft nude mouse model.
Conclusions: HDAC1/FOXK1 upregulation and miR-33a silencing are new mechanisms of EGFR-TKI resistance in NSCLC.
(© 2024. The Author(s).)

Oncol Rep. 2018 Jul;40(1):346-354. (PMID: 29767267)
Cancer Res. 2006 Jan 15;66(2):944-50. (PMID: 16424029)
Toxicol Sci. 2013 Jul;134(1):26-38. (PMID: 23748240)
Genomics Proteomics Bioinformatics. 2022 Jun;20(3):446-454. (PMID: 35643191)
Clin Transl Oncol. 2018 Apr;20(4):457-466. (PMID: 28871425)
Oncogene. 2019 Sep;38(37):6399-6413. (PMID: 31324888)
Oncogene. 2020 Dec;39(49):7181-7195. (PMID: 33037411)
Transl Oncol. 2022 Feb;16:101312. (PMID: 34922087)
Molecules. 2021 Jun 28;26(13):. (PMID: 34203519)
Mol Cancer Ther. 2007 Sep;6(9):2515-24. (PMID: 17876048)
N Engl J Med. 2009 Sep 3;361(10):947-57. (PMID: 19692680)
Bioorg Chem. 2021 Dec;117:105407. (PMID: 34653945)
Int J Mol Sci. 2021 Jul 08;22(14):. (PMID: 34298969)
Clin Cancer Res. 2008 Mar 15;14(6):1669-77. (PMID: 18347167)
Metabolites. 2021 Nov 20;11(11):. (PMID: 34822450)
Chem Biol Interact. 2022 Jan 25;352:109778. (PMID: 34929181)
Hum Exp Toxicol. 2021 Dec;40(12_suppl):S318-S330. (PMID: 34477002)
Nat Commun. 2020 Sep 15;11(1):4639. (PMID: 32934238)
Arch Biochem Biophys. 2023 Jul 1;742:109620. (PMID: 37142077)
Front Cell Dev Biol. 2021 Aug 02;9:669132. (PMID: 34409025)
Mol Cell Biol. 2007 Jul;27(13):4784-95. (PMID: 17470557)
Aging (Albany NY). 2020 Apr 8;12(7):6129-6150. (PMID: 32268297)
Mol Cancer Ther. 2008 Jul;7(7):1923-30. (PMID: 18606719)
N Engl J Med. 2018 Jan 11;378(2):113-125. (PMID: 29151359)
J Theor Biol. 2019 Mar 7;464:63-71. (PMID: 30593826)
Int J Oncol. 2021 Nov;59(5):. (PMID: 34558640)
Cells. 2019 Nov 22;8(12):. (PMID: 31771093)
Medicine (Baltimore). 2017 Aug;96(31):e7663. (PMID: 28767587)
J Clin Oncol. 2016 Oct 1;34(28):3375-82. (PMID: 27354477)
Oncol Rep. 2016 Jul;36(1):589-97. (PMID: 27221381)
Neoplasia. 2017 Aug;19(8):649-658. (PMID: 28732212)
Cancer. 2020 Jan 1;126(9):2024-2033. (PMID: 31999837)
Br J Clin Pharmacol. 2021 Dec;87(12):4577-4597. (PMID: 33971031)
Epigenetics. 2023 Dec;18(1):2237761. (PMID: 37499114)
Cancer Med. 2018 May;7(5):1955-1966. (PMID: 29573196)
Sci Rep. 2020 Aug 19;10(1):13988. (PMID: 32814794)
Cell Mol Life Sci. 2022 Jul 25;79(8):446. (PMID: 35876890)
Anticancer Res. 2021 Sep;41(9):4353-4364. (PMID: 34475055)
J Thorac Oncol. 2016 Apr;11(4):556-65. (PMID: 26724471)
Cell Death Dis. 2020 Oct 14;11(10):858. (PMID: 33056982)
Br J Cancer. 2020 Mar;122(7):1050-1058. (PMID: 32020063)
Am J Cancer Res. 2018 Sep 01;8(9):1812-1822. (PMID: 30323973)
Int J Oncol. 2020 Oct;57(4):1027-1038. (PMID: 32945468)
Recent Pat Anticancer Drug Discov. 2023;18(4):506-516. (PMID: 36464873)
Cancer Biol Med. 2022 Feb 22;19(8):. (PMID: 35188360)
Biochem Biophys Res Commun. 2017 Jan 22;482(4):582-589. (PMID: 27856248)
Int J Cancer. 2014 Nov 1;135(9):2223-31. (PMID: 24668305)
Mol Cancer. 2020 Jan 15;19(1):9. (PMID: 31941509)
Cancer Res. 2019 Apr 15;79(8):1769-1783. (PMID: 30842103)
Cancer Res. 2013 Apr 15;73(8):2428-34. (PMID: 23382048)
Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12228-32. (PMID: 20566875)
Oncogene. 2020 Feb;39(9):1969-1982. (PMID: 31772327)
Clin Cancer Res. 2015 Jan 15;21(2):428-38. (PMID: 25593344)
Sci Signal. 2013 Apr 02;6(269):pl1. (PMID: 23550210)
Biomed Pharmacother. 2020 Jun;126:110019. (PMID: 32151944)
Toxicol Appl Pharmacol. 2019 Sep 1;378:114603. (PMID: 31152816)

82102916 Innovative Research Group Project of the National Natural Science Foundation of China; 82073393 Innovative Research Group Project of the National Natural Science Foundation of China; LHGJ20210176 Henan Provincial Science and Technology Research Project; KC2021-JX-0186-44 Beijing Science and Technology Innovation Fund

Keywords: EGFR-TKI; FOXK1; HDAC1; Lung adenocarcinoma; miR-33a

EC 2.7.10.1 (ErbB Receptors)
0 (Forkhead Transcription Factors)
0 (FOXK1 protein, human)
S65743JHBS (Gefitinib)
EC 3.5.1.98 (HDAC1 protein, human)
EC 3.5.1.98 (Histone Deacetylase 1)
0 (MicroRNAs)
0 (MIRN33a microRNA, human)
0 (Protein Kinase Inhibitors)

Date Created: 20240828 Date Completed: 20240829 Latest Revision: 20240902

20240902

PMC11350990

10.1186/s12967-024-05563-3

39198847