title: DNA damage response (DDR) via NKX3.1 expression in prostate cells.
abstract: It has been reported that NKX3.1 an androgen-regulated homeobox gene restricted to prostate and testicular tissues, encodes a homeobox protein, which transcriptionally regulates oxidative damage responses and enhances topoisomerase I re-ligation by a direct interaction with the ATM protein in prostate cells. In this study, we aimed to investigate the role of NKX3.1 in DNA double-strand break (DSB) repair. We demonstrate that the DNA damage induced by CPT-11 (irinotecan, a topo I inhibitor), doxorubicin (a topo II inhibitor), and H2O2 (a mediator of oxidative damage), but not by etoposide (another topo II inhibitor), is negatively influenced by NKX3.1 expression. We also examined γH2AX((S139)) foci formation and observed that the overexpression of NKX3.1 resulted a remarkable decrease in the formation of γH2AX((S139)) foci. Intriguingly, we observed in NKX3.1 silencing studies that the depletion of NKX3.1 correlated with a significant decrease in the levels of p-ATM((S1981)) and γH2AX((S139)). The data imply that the DNA damage response (DDR) can be altered, perhaps via a decrease in the topoisomerase I re-ligation function; this is consistent with the physical association of NKX3.1 with DDR mediators upon treatment of both PC-3 and LNCaP cells with CPT-11. Furthermore, the depletion of NKX3.1 resulted in a G1/S progression via the facilitation of an increase in E2F stabilization concurrent with the suppressed DDR. Thus, the topoisomerase I inhibitor-mediated DNA damage enhanced the physical association of NKX3.1 with γH2AX((S139)) on the chromatin in LNCaP cells, whereas NKX3.1 in the soluble fraction was associated with p-ATM((S1981)) and RAD50 in these cells. Overall, the data suggest that androgens and NKX3.1 expression regulate the progression of the cell cycle and concurrently activate the DDR. Therefore, androgen withdrawal may augment the development of an error-prone phenotype and, subsequently, the loss of DNA damage control during prostate cancer progression.
authors.affiliation: Ege University, Faculty of Engineering, Department of Bioengineering, Cancer Biology Laboratory, Bornova, Izmir, Turkey. Electronic address: burcu_erbaykent@yahoo.com.
authors.forename: Burcu
authors.initials: B
authors.lastname: Erbaykent-Tepedelen
authors.affiliation: Ege University, Faculty of Engineering, Department of Bioengineering, Cancer Biology Laboratory, Bornova, Izmir, Turkey. Electronic address: seldakaramil@yahoo.com.
authors.forename: Selda
authors.initials: S
authors.lastname: Karamil
authors.affiliation: Ege University, Faculty of Pharmacy, Department of Pharmacology, Bornova, Izmir, Turkey. Electronic address: korkmaz_ceren@yahoo.com.
authors.forename: Ceren
authors.initials: C
authors.lastname: Gonen-Korkmaz
authors.affiliation: Ege University, Faculty of Engineering, Department of Bioengineering, Cancer Biology Laboratory, Bornova, Izmir, Turkey. Electronic address: ks_korkmaz@yahoo.com.
authors.forename: Kemal S
authors.initials: KS
authors.lastname: Korkmaz
mesh_terms: D017766:Acid Anhydride Hydrolases; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000077146:Irinotecan; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology; D010766:Phosphorylation; D011471:Prostatic Neoplasms; D011499:Protein Processing, Post-Translational; D045165:Testosterone Congeners / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology*
chemical_list: C530104:CCND1 protein, human; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D018398:Homeodomain Proteins; D009153:Mutagens; C491178:NKX3-1 protein, human; D045165:Testosterone Congeners; D014157:Transcription Factors; D019938:Cyclin D1; D015741:Metribolone; D005047:Etoposide; D000077146:Irinotecan; D004317:Doxorubicin; D006861:Hydrogen Peroxide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes; D002166:Camptothecin
keywords: ATM phosphorylation; Doxorubicin; Etoposide; H2AX; Irinotecan (CPT-11)