Estrogen-Dependent Dynamic Profile of eNOS-DNA Associations in Prostate Cancer

Simona Nanni, Aurora Aiello, Agnese Re, Alessandro Guffanti, Valentina Benvenuti, Claudia Colussi, Luis Jaime Castro-Vega, Armando Felsani, Arturo Londono-Vallejo, Maurizio C. Capogrossi, Silvia Bacchetti, Carlo Gaetano, Alfredo Pontecorvi, Antonella Farsetti

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ERβ) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1. the eNOS-bound regions (peaks) are widely distributed across the genome encompassing multiple transcription factors binding sites, including Estrogen Response Elements. 2. E2 increased the number of peaks, indicating hormone-dependent eNOS re-localization. 3. Peak distribution was similar with/without E2 with ≈ 55% of them in extragenic DNA regions and an intriguing involvement of the 5′ domain of several miRs deregulated in PCa. Numerous potentially novel eNOS-targeted genes have been identified suggesting that eNOS participates in the regulation of large gene sets. The parallel finding of downregulation of a cluster of miRs, including miR-34a, in PCa cells associated with poor outcome led us to unveil a molecular link between eNOS and SIRT1, an epigenetic regulator of aging and tumorigenicity, negatively regulated by miR-34a and in turn activating eNOS. E2 potentiates miR-34a downregulation thus enhancing SIRT1 expression, depicting a novel eNOS/SIRT1 interplay fine-tuned by E2-activated ER signaling, and suggesting that eNOS may play an important role in aggressive PCa.

Original languageEnglish
Article numbere62522
JournalPLoS One
Volume8
Issue number5
DOIs
Publication statusPublished - May 3 2013

Fingerprint

prostatic neoplasms
estrogens
Prostatic Neoplasms
Estrogens
Genes
Estrogen Receptor beta
DNA
Chromatin
chromatin
hypoxia
Down-Regulation
Response Elements
Chromatin Assembly and Disassembly
genes
response elements
Tumors
Transcription Factors
Epigenomics
epigenetics
Aging of materials

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Nanni, S., Aiello, A., Re, A., Guffanti, A., Benvenuti, V., Colussi, C., ... Farsetti, A. (2013). Estrogen-Dependent Dynamic Profile of eNOS-DNA Associations in Prostate Cancer. PLoS One, 8(5), [e62522]. https://doi.org/10.1371/journal.pone.0062522

Estrogen-Dependent Dynamic Profile of eNOS-DNA Associations in Prostate Cancer. / Nanni, Simona; Aiello, Aurora; Re, Agnese; Guffanti, Alessandro; Benvenuti, Valentina; Colussi, Claudia; Castro-Vega, Luis Jaime; Felsani, Armando; Londono-Vallejo, Arturo; Capogrossi, Maurizio C.; Bacchetti, Silvia; Gaetano, Carlo; Pontecorvi, Alfredo; Farsetti, Antonella.

In: PLoS One, Vol. 8, No. 5, e62522, 03.05.2013.

Research output: Contribution to journalArticle

Nanni, S, Aiello, A, Re, A, Guffanti, A, Benvenuti, V, Colussi, C, Castro-Vega, LJ, Felsani, A, Londono-Vallejo, A, Capogrossi, MC, Bacchetti, S, Gaetano, C, Pontecorvi, A & Farsetti, A 2013, 'Estrogen-Dependent Dynamic Profile of eNOS-DNA Associations in Prostate Cancer', PLoS One, vol. 8, no. 5, e62522. https://doi.org/10.1371/journal.pone.0062522
Nanni S, Aiello A, Re A, Guffanti A, Benvenuti V, Colussi C et al. Estrogen-Dependent Dynamic Profile of eNOS-DNA Associations in Prostate Cancer. PLoS One. 2013 May 3;8(5). e62522. https://doi.org/10.1371/journal.pone.0062522
Nanni, Simona ; Aiello, Aurora ; Re, Agnese ; Guffanti, Alessandro ; Benvenuti, Valentina ; Colussi, Claudia ; Castro-Vega, Luis Jaime ; Felsani, Armando ; Londono-Vallejo, Arturo ; Capogrossi, Maurizio C. ; Bacchetti, Silvia ; Gaetano, Carlo ; Pontecorvi, Alfredo ; Farsetti, Antonella. / Estrogen-Dependent Dynamic Profile of eNOS-DNA Associations in Prostate Cancer. In: PLoS One. 2013 ; Vol. 8, No. 5.
@article{3dde51c3a88d43459ce8ebf85886f01b,
title = "Estrogen-Dependent Dynamic Profile of eNOS-DNA Associations in Prostate Cancer",
abstract = "In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ERβ) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1. the eNOS-bound regions (peaks) are widely distributed across the genome encompassing multiple transcription factors binding sites, including Estrogen Response Elements. 2. E2 increased the number of peaks, indicating hormone-dependent eNOS re-localization. 3. Peak distribution was similar with/without E2 with ≈ 55{\%} of them in extragenic DNA regions and an intriguing involvement of the 5′ domain of several miRs deregulated in PCa. Numerous potentially novel eNOS-targeted genes have been identified suggesting that eNOS participates in the regulation of large gene sets. The parallel finding of downregulation of a cluster of miRs, including miR-34a, in PCa cells associated with poor outcome led us to unveil a molecular link between eNOS and SIRT1, an epigenetic regulator of aging and tumorigenicity, negatively regulated by miR-34a and in turn activating eNOS. E2 potentiates miR-34a downregulation thus enhancing SIRT1 expression, depicting a novel eNOS/SIRT1 interplay fine-tuned by E2-activated ER signaling, and suggesting that eNOS may play an important role in aggressive PCa.",
author = "Simona Nanni and Aurora Aiello and Agnese Re and Alessandro Guffanti and Valentina Benvenuti and Claudia Colussi and Castro-Vega, {Luis Jaime} and Armando Felsani and Arturo Londono-Vallejo and Capogrossi, {Maurizio C.} and Silvia Bacchetti and Carlo Gaetano and Alfredo Pontecorvi and Antonella Farsetti",
year = "2013",
month = "5",
day = "3",
doi = "10.1371/journal.pone.0062522",
language = "English",
volume = "8",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "5",

}

TY - JOUR

T1 - Estrogen-Dependent Dynamic Profile of eNOS-DNA Associations in Prostate Cancer

AU - Nanni, Simona

AU - Aiello, Aurora

AU - Re, Agnese

AU - Guffanti, Alessandro

AU - Benvenuti, Valentina

AU - Colussi, Claudia

AU - Castro-Vega, Luis Jaime

AU - Felsani, Armando

AU - Londono-Vallejo, Arturo

AU - Capogrossi, Maurizio C.

AU - Bacchetti, Silvia

AU - Gaetano, Carlo

AU - Pontecorvi, Alfredo

AU - Farsetti, Antonella

PY - 2013/5/3

Y1 - 2013/5/3

N2 - In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ERβ) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1. the eNOS-bound regions (peaks) are widely distributed across the genome encompassing multiple transcription factors binding sites, including Estrogen Response Elements. 2. E2 increased the number of peaks, indicating hormone-dependent eNOS re-localization. 3. Peak distribution was similar with/without E2 with ≈ 55% of them in extragenic DNA regions and an intriguing involvement of the 5′ domain of several miRs deregulated in PCa. Numerous potentially novel eNOS-targeted genes have been identified suggesting that eNOS participates in the regulation of large gene sets. The parallel finding of downregulation of a cluster of miRs, including miR-34a, in PCa cells associated with poor outcome led us to unveil a molecular link between eNOS and SIRT1, an epigenetic regulator of aging and tumorigenicity, negatively regulated by miR-34a and in turn activating eNOS. E2 potentiates miR-34a downregulation thus enhancing SIRT1 expression, depicting a novel eNOS/SIRT1 interplay fine-tuned by E2-activated ER signaling, and suggesting that eNOS may play an important role in aggressive PCa.

AB - In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ERβ) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1. the eNOS-bound regions (peaks) are widely distributed across the genome encompassing multiple transcription factors binding sites, including Estrogen Response Elements. 2. E2 increased the number of peaks, indicating hormone-dependent eNOS re-localization. 3. Peak distribution was similar with/without E2 with ≈ 55% of them in extragenic DNA regions and an intriguing involvement of the 5′ domain of several miRs deregulated in PCa. Numerous potentially novel eNOS-targeted genes have been identified suggesting that eNOS participates in the regulation of large gene sets. The parallel finding of downregulation of a cluster of miRs, including miR-34a, in PCa cells associated with poor outcome led us to unveil a molecular link between eNOS and SIRT1, an epigenetic regulator of aging and tumorigenicity, negatively regulated by miR-34a and in turn activating eNOS. E2 potentiates miR-34a downregulation thus enhancing SIRT1 expression, depicting a novel eNOS/SIRT1 interplay fine-tuned by E2-activated ER signaling, and suggesting that eNOS may play an important role in aggressive PCa.

UR - http://www.scopus.com/inward/record.url?scp=84877083199&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84877083199&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0062522

DO - 10.1371/journal.pone.0062522

M3 - Article

VL - 8

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 5

M1 - e62522

ER -