title: MnTE-2-PyP reduces prostate cancer growth and metastasis by suppressing p300 activity and p300/HIF-1/CREB binding to the promoter region of the PAI-1 gene.
abstract: To improve radiation therapy-induced quality of life impairments for prostate cancer patients, the development of radio-protectors is needed. Our previous work has demonstrated that MnTE-2-PyP significantly protects urogenital tissues from radiation-induced damage. So, in order for MnTE-2-PyP to be used clinically as a radio-protector, it is fully necessary to explore the effect of MnTE-2-PyP on human prostate cancer progression. MnTE-2-PyP inhibited prostate cancer growth in the presence and absence of radiation and also inhibited prostate cancer migration and invasion. MnTE-2-PyP altered p300 DNA binding, which resulted in the inhibition of HIF-1β and CREB signaling pathways. Accordingly, we also found that MnTE-2-PyP reduced the expression of three genes regulated by HIF-1β and/or CREB: TGF-β2, FGF-1 and PAI-1. Specifically, MnTE-2-PyP decreased p300 complex binding to a specific HRE motif within the PAI-1 gene promoter region, suppressed H3K9 acetylation, and consequently, repressed PAI-1 expression. Mechanistically, less p300 transcriptional complex binding is not due to the reduction of binding between p300 and HIF-1/CREB transcription factors, but through inhibiting the binding of HIF-1/CREB transcription factors to DNA. Our data provide an in depth mechanism by which MnTE-2-PyP reduces prostate cancer growth and metastasis, which validates the clinical use of MnTE-2-PyP as a radio-protector to enhance treatment outcomes in prostate cancer radiotherapy.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Tong
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO 80206, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Weaver
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Kosmacek
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, CO 80206, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: O'Connor
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, CO 80206, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Harmacek
authors.affiliation: Department of Pediatrics, University of Colorado Health Sciences Center, Aurora, CO 80045, USA.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Venkataraman
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA. Electronic address: becky.deegan@unmc.edu.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Oberley-Deegan
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins; D050881:E1A-Associated p300 Protein / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008665:Metalloporphyrins / Q000008:administration & dosage*; D009362:Neoplasm Metastasis; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D011827:Radiation; D011837:Radiation-Protective Agents / Q000008:administration & dosage
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008665:Metalloporphyrins; D017395:Plasminogen Activator Inhibitor 1; D011837:Radiation-Protective Agents; C051321:SERPINE1 protein, human; C520506:manganese tetrakis-(N-ethyl-2 pyridyl) porphyrin; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human
keywords: CREB; HIF-1β; MnTE-2-PyP; PAI-1; p300