Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Pharmaceutical Biotechnology
  4. Volume 26, Issue 6
  5. Article
Volume 26, Issue 6
  • ISSN: 1389-2010
  • E-ISSN: 1873-4316
file format text download EPUB
file format pdf download PDF
side by side viewer icon HTML

Abstract

Objective

This study aimed to investigate the effect of dihydroartemisinin (DHA) on DU145 cells and the role of NR2F2 (COUP-TFII) and its potential target genes in this process.

Methods

GSE122625 was used to identify differentially expressed genes (DEGs) between the DHA-treated and control groups. Protein-protein interaction (PPI) network analysis was performed to identify hub genes, and the ChEA3 database was used to identify potential transcription factors. qRT-PCR and Western blot were used to validate the expression of genes of interest and functional assays were performed to evaluate the effect of DHA on DU145 and PC-3 cells. To solidify the regulatory relationship of NR2F2 with EFNB2, EBF1, ETS1, and VEGFA, a Chromatin Immunoprecipitation (ChIP) experiment was performed.

Results

We identified 85 DEGs in DU145 cells treated with DHA, and PPI network analysis identified NR2F2 as a hub gene and potential transcription factor. The regulatory network of NR2F2 and its potential target genes (EFNB2, EBF1, ETS1, and VEGFA) was constructed, and the expression of these genes was upregulated in DHA-treated cells compared to control cells. Functional assays showed that DHA treatment inhibited epithelial-mesenchymal transition, reduced inflammation, and promoted apoptosis in DU145 and PC-3 cells. Furthermore, NR2F2 knockdown receded the DHA-induced upregulation of target genes and functional changes of DU145 and PC-3 cells. The outcomes of ChIP unequivocally pointed to a positive regulatory role of NR2F2 in these gene expressions.

Conclusion

Our study suggests that DHA treatment affects the functions of DU145 and PC-3 cells by regulating the expression of NR2F2 and its potential target genes, and NR2F2 may serve as a potential therapeutic target for prostate cancer.

© 2025 Bentham Science Publishers
© 2025 The Author(s). Published by Bentham Science Publishers. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
Loading

Article metrics loading...

/content/journals/cpb/10.2174/0113892010311317240919061821
2024-10-03
2025-07-03

  • From This Site

    /content/journals/cpb/10.2174/0113892010311317240919061821
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
The full text of this item is not currently available.

References

  1. WangL. LuB. HeM. WangY. WangZ. DuL. Prostate Cancer Incidence and Mortality: Global Status and Temporal Trends in 89 Countries From 2000 to 2019.Front. Public Health20221081104410.3389/fpubh.2022.81104435252092
     [Google Scholar]
  2. CulpM.B. SoerjomataramI. EfstathiouJ.A. BrayF. JemalA. Recent Global Patterns in Prostate Cancer Incidence and Mortality Rates.Eur. Urol.2020771385210.1016/j.eururo.2019.08.00531493960
     [Google Scholar]
  3. TaittH.E. Global Trends and Prostate Cancer: A Review of Incidence, Detection, and Mortality as Influenced by Race, Ethnicity, and Geographic Location.Am. J. Men Health20181261807182310.1177/155798831879827930203706
     [Google Scholar]
  4. DaiX. ZhangX. ChenW. ChenY. ZhangQ. MoS. LuJ. Dihydroartemisinin: A Potential Natural Anticancer Drug.Int. J. Biol. Sci.202117260362210.7150/ijbs.5036433613116
     [Google Scholar]
  5. YongJ. LuC. OlatundeO.Z. An Overview of Dihydroartemisinin as a Promising Lead Compound for Development of Anticancer Agents.Mini Rev. Med. Chem.202323326528910.2174/138955752266622042512492335469566
     [Google Scholar]
  6. GourR. AhmadF. PrajapatiS.K. GiriS.K. Lal KarnaS.K. KarthaK.P.R. PokharelY.R. Synthesis of novel S-linked dihydroartemisinin derivatives and evaluation of their anticancer activity.Eur. J. Med. Chem.201917855257010.1016/j.ejmech.2019.06.01831216504
     [Google Scholar]
  7. HeQ. ShiJ. ShenX.L. AnJ. SunH. WangL. HuY.J. SunQ. FuL.C. SheikhM.S. HuangY. Dihydroartemisinin upregulates death receptor 5 expression and cooperates with TRAIL to induce apoptosis in human prostate cancer cells.Cancer Biol. Ther.201091081982410.4161/cbt.9.10.1155220224297
     [Google Scholar]
  8. DuS. XuG. ZouW. XiangT. LuoZ. Effect of dihydroartemisinin on UHRF1 gene expression in human prostate cancer PC-3 cells.Anticancer Drugs201728438439110.1097/CAD.000000000000046928059831
     [Google Scholar]
  9. DeyA. SenS. MaulikU. Study of transcription factor druggabilty for prostate cancer using structure information, gene regulatory networks and protein moonlighting.Brief. Bioinform.2022231bbab46510.1093/bib/bbab46534849560
     [Google Scholar]
  10. SinghA. HappelC. MannaS.K. Acquaah-MensahG. CarrereroJ. KumarS. NasipuriP. KrauszK.W. WakabayashiN. DewiR. BorosL.G. GonzalezF.J. GabrielsonE. WongK.K. GirnunG. BiswalS. Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis.J. Clin. Invest.201312372921293410.1172/JCI6635323921124
     [Google Scholar]
  11. KumarV. ChengP. CondamineT. MonyS. LanguinoL.R. McCaffreyJ.C. HocksteinN. GuarinoM. MastersG. PenmanE. DenstmanF. XuX. AltieriD.C. DuH. YanC. GabrilovichD.I. CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation.Immunity201644230331510.1016/j.immuni.2016.01.01426885857
     [Google Scholar]
  12. BushwellerJ.H. Targeting transcription factors in cancer — from undruggable to reality.Nat. Rev. Cancer2019191161162410.1038/s41568‑019‑0196‑731511663
     [Google Scholar]
  13. XiaT. LiuS. XuG. ZhouS. LuoZ. Dihydroartemisinin induces cell apoptosis through repression of UHRF1 in prostate cancer cells.Anticancer Drugs2022331e113e12410.1097/CAD.000000000000115634387595
     [Google Scholar]
  14. LiangY. WuX. LeeJ. YuD. SuJ. GuoM. MengN. QinJ. FanX. lncRNA NR2F2-AS1 inhibits the methylation of miR-494 to regulate oral squamous cell carcinoma cell proliferation.Arch. Oral Biol.202213410531610.1016/j.archoralbio.2021.10531634896865
     [Google Scholar]
  15. MaL. HuangM. LiaoX. CaiX. WuQ. NR2F2 Regulates Cell Proliferation and Immunomodulation in Whartons’ Jelly Stem Cells.Genes (Basel)2022138145810.3390/genes1308145836011369
     [Google Scholar]
  16. MauriF. SchepkensC. LapougeG. DrogatB. SongY. PastushenkoI. RoriveS. BlondeauJ. GolsteinS. BarecheY. MiglianicoM. NkusiE. RozziM. MoersV. BrisebarreA. RaphaëlM. DuboisC. AllardJ. DurduB. RibeiroF. SotiriouC. SalmonI. VakiliJ. BlanpainC. NR2F2 controls malignant squamous cell carcinoma state by promoting stemness and invasion and repressing differentiation.Nat. Cancer20212111152116910.1038/s43018‑021‑00287‑535122061
     [Google Scholar]
  17. CaiY.Y. NR2F2 mediates cell growth and endocrine resistance in NF1 loss, ER+ breast cancer.Cancer Res.20228212
     [Google Scholar]
  18. Cristina Fugazza Gloria Barbarani Sudharshan Elangovan Serena Giolitto Isaura Font-Monclus Laura Manunza John Strouboulis Claudio Cantù Fabio Gasparri Yukio Nakamura Sergio Ottolenghi Paolo Moi NakamuraY. OttolenghiS. MoiP. RonchiA.E. The Coup-TFII orphan nuclear receptor is an activator of the γ-globin gene.Haematologica2020106247448210.3324/haematol.2019.24122432107331
     [Google Scholar]
  19. PolvaniS. PepeS. MilaniS. GalliA. COUP-TFII in Health and Disease.Cells20199110110.3390/cells901010131906104
     [Google Scholar]
  20. BaoY. LuY. FengW. YuH. GuoH. TaoY. ShiQ. ChenW. WangX. COUP‑TFII promotes epithelial‑mesenchymal transition by inhibiting miR‑34a expression in colorectal cancer.Int. J. Oncol.20195441337134410.3892/ijo.2019.471830968145
     [Google Scholar]
  21. ErdősE. BálintB.L. COUP-TFII is a modulator of cell-type-specific genetic programs based on genomic localization maps.J. Biotechnol.2019301111710.1016/j.jbiotec.2019.05.30531158411
     [Google Scholar]
  22. AshrafU.M. SanchezE.R. KumarasamyS. COUP-TFII revisited: Its role in metabolic gene regulation.Steroids2019141636910.1016/j.steroids.2018.11.01330481528
     [Google Scholar]
  23. LinS.C. KaoC.Y. LeeH.J. CreightonC.J. IttmannM.M. TsaiS.J. TsaiS.Y. TsaiM.J. Dysregulation of miRNAs-COUP-TFII-FOXM1-CENPF axis contributes to the metastasis of prostate cancer.Nat. Commun.2016711141810.1038/ncomms1141827108958
     [Google Scholar]
  24. ZhangW. LiuJ. QiuJ. FuX. TangQ. YangF. ZhaoZ. WangH. MicroRNA-382 inhibits prostate cancer cell proliferation and metastasis through targeting COUP-TFII.Oncol. Rep.20163663707371510.3892/or.2016.514127748848
     [Google Scholar]
  25. YunS.H. ParkJ.I. Recent progress on the role and molecular mechanism of chicken ovalbumin upstream promoter-transcription factor II in cancer.J. Int. Med. Res.202048410.1177/030006052091923632338091
     [Google Scholar]
  26. QinJ. WuS.P. CreightonC.J. DaiF. XieX. ChengC.M. FrolovA. AyalaG. LinX. FengX.H. IttmannM.M. TsaiS.J. TsaiM.J. TsaiS.Y. COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis.Nature2013493743123624010.1038/nature1167423201680
     [Google Scholar]
  27. LilisI. The expression of p-mTOR and COUP-TFII correlates with increased lymphangiogenesis and lymph node metastasis in prostate adenocarcinoma.Urol Oncol.2018366311.e27311.e3510.1016/j.urolonc.2018.02.007
     [Google Scholar]
  28. WangL. XuM. QinJ. LinS.C. LeeH.J. TsaiS.Y. TsaiM.J. MPC1, a key gene in cancer metabolism, is regulated by COUPTFII in human prostate cancer.Oncotarget2016712146731468310.18632/oncotarget.740526895100
     [Google Scholar]
  29. QinJ. TsaiS. TsaiM.J. COUP-TFII, a prognostic marker and therapeutic target for prostate cancer.Asian J. Androl.201315336036110.1038/aja.2013.1223435470
     [Google Scholar]
  30. LeeH.C. OuC.H. HuangY.C. HouP.C. CreightonC.J. LinY.S. HuC.Y. LinS.C. YAP1 overexpression contributes to the development of enzalutamide resistance by induction of cancer stemness and lipid metabolism in prostate cancer.Oncogene202140132407242110.1038/s41388‑021‑01718‑433664454
     [Google Scholar]
  31. SafeS. JinU.H. HedrickE. ReederA. LeeS.O. Minireview: role of orphan nuclear receptors in cancer and potential as drug targets.Mol. Endocrinol.201428215717210.1210/me.2013‑129124295738
     [Google Scholar]
  32. WangL. ChengC.M. QinJ. XuM. KaoC.Y. ShiJ. YouE. GongW. RosaL.P. ChaseP. ScampaviaL. MadouxF. SpicerT. HodderP. XuH.E. TsaiS.Y. TsaiM.J. Small-molecule inhibitor targeting orphan nuclear receptor COUP-TFII for prostate cancer treatment.Sci. Adv.2020618eaaz803110.1126/sciadv.aaz803132494682
     [Google Scholar]
  33. XuC. GuL. KuerbanjiangM. JiangC. HuL. LiuY. XueH. LiJ. ZhangZ. XuQ. Adaptive activation of EFNB2/EPHB4 axis promotes post-metastatic growth of colorectal cancer liver metastases by LDLR-mediated cholesterol uptake.Oncogene20234229911210.1038/s41388‑022‑02519‑z36376513
     [Google Scholar]
  34. InoueC. MikiY. Saito-KoyamaR. KobayashiK. SeyamaK. OkadaY. SasanoH. Vasohibin-1 and -2 in pulmonary lymphangioleiomyomatosis (LAM) cells associated with angiogenic and prognostic factors.Pathol. Res. Pract.202223015375810.1016/j.prp.2022.15375835026646
     [Google Scholar]
  35. ShuangO. ZhouJ. CaiZ. LiaoL. WangY. WangW. XuM. EBF1-mediated up-regulation of lncRNA FGD5-AS1 facilitates osteosarcoma progression by regulating miR-124-3p/G3BP2 axis as a ceRNA.J. Orthop. Surg. Res.202217133210.1186/s13018‑022‑03181‑735761386
     [Google Scholar]
  36. LuoH. YangL. LiuC. WangX. DongQ. LiuL. WeiQ. TMPO-AS1/miR-98-5p/EBF1 feedback loop contributes to the progression of bladder cancer.Int. J. Biochem. Cell Biol.202012210570210.1016/j.biocel.2020.10570232087328
     [Google Scholar]
  37. QiuK. ZhengZ. HuangY. Long intergenic noncoding RNA 00844 promotes apoptosis and represses proliferation of prostate cancer cells through upregulating GSTP1 by recruiting EBF1.J. Cell. Physiol.2020235118472848510.1002/jcp.2969032329523
     [Google Scholar]
  38. XuS. GeJ. ZhangZ. ZhouW. MiR-129 inhibits cell proliferation and metastasis by targeting ETS1 via PI3K/AKT/mTOR pathway in prostate cancer.Biomed. Pharmacother.20179663464110.1016/j.biopha.2017.10.03729035829
     [Google Scholar]
  39. GuY. WuS. ChongY. GuanB. LiL. HeD. WangX. WangB. WuK. DAB2IP regulates intratumoral testosterone synthesis and CRPC tumor growth by ETS1/AKR1C3 signaling.Cell. Signal.20229511033610.1016/j.cellsig.2022.11033635452821
     [Google Scholar]
  40. LuG. ZhangQ. HuangY. SongJ. TomainoR. EhrenbergerT. LimE. LiuW. BronsonR.T. BowdenM. BrockJ. KropI.E. DillonD.A. GygiS.P. MillsG.B. RichardsonA.L. SignorettiS. YaffeM.B. KaelinW.G.Jr Phosphorylation of ETS1 by Src family kinases prevents its recognition by the COP1 tumor suppressor.Cancer Cell201426222223410.1016/j.ccr.2014.06.02625117710
     [Google Scholar]
  41. MaJ. ChenX. ChenY. TaoN. QinZ. Ligustilide Inhibits Tumor Angiogenesis by Downregulating VEGFA Secretion from Cancer-Associated Fibroblasts in Prostate Cancer via TLR4.Cancers (Basel)20221410240610.3390/cancers1410240635626012
     [Google Scholar]
  42. GanapathyK. StaklinskiS. HasanM.F. OttmanR. AndlT. BerglundA.E. ParkJ.Y. ChakrabartiR. Multifaceted Function of MicroRNA-299-3p Fosters an Antitumor Environment Through Modulation of Androgen Receptor and VEGFA Signaling Pathways in Prostate Cancer.Sci. Rep.2020101516710.1038/s41598‑020‑62038‑332198489
     [Google Scholar]
  43. MushimiyimanaI. Tomas BoschV. NiskanenH. DownesN.L. MoreauP.R. HartiganK. Ylä-HerttualaS. Laham-KaramN. KaikkonenM.U. Genomic Landscapes of Noncoding RNAs Regulating VEGFA and VEGFC Expression in Endothelial Cells.Mol. Cell. Biol.2021417e00594-2010.1128/MCB.00594‑2033875575
     [Google Scholar]
  44. MuH.Q. HeY.H. WangS.B. YangS. WangY.J. NanC.J. BaoY.F. XieQ.P. ChenY.H. MiR-130b/TNF-α/NF-κB/VEGFA loop inhibits prostate cancer angiogenesis.Clin. Transl. Oncol.202022111112110.1007/s12094‑019‑02217‑531667686
     [Google Scholar]
  45. PaccezJ.D. DuncanK. SekarD. CorreaR.G. WangY. GuX. BashinM. ChibaleK. LibermannT.A. ZerbiniL.F. Dihydroartemisinin inhibits prostate cancer via JARID2/miR-7/miR-34a-dependent downregulation of Axl.Oncogenesis2019831410.1038/s41389‑019‑0122‑630783079
     [Google Scholar]
/content/journals/cpb/10.2174/0113892010311317240919061821
Loading
Dihydroartemisinin Modulates Prostate Cancer Progression by Regulating Multiple Genes via the Transcription Factor NR2F2
Current Pharmaceutical Biotechnology 26, 935 (2025); https://doi.org/10.2174/0113892010311317240919061821
/content/journals/cpb/10.2174/0113892010311317240919061821
/content/journals/cpb/10.2174/0113892010311317240919061821
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): DHA; DU145; NR2F2; PC-3 cells; prostate cancer; transcription factor

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test