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.
authors: Department of Experimental Oncology, National Cancer Institute Regina Elena, Rome, Italy.
authors: Simona
authors: S
authors: Nanni
authors: Aurora
authors: A
authors: Aiello
authors: Agnese
authors: A
authors: Re
authors: Alessandro
authors: A
authors: Guffanti
authors: Valentina
authors: V
authors: Benvenuti
authors: Claudia
authors: C
authors: Colussi
authors: Luis Jaime
authors: LJ
authors: Castro-Vega
authors: Armando
authors: A
authors: Felsani
authors: Arturo
authors: A
authors: Londono-Vallejo
authors: Maurizio C
authors: MC
authors: Capogrossi
authors: Silvia
authors: S
authors: Bacchetti
authors: Carlo
authors: C
authors: Gaetano
authors: Alfredo
authors: A
authors: Pontecorvi
authors: Antonella
authors: A
authors: Farsetti
mesh_terms: D002277:Carcinoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000235:genetics* / Q000378:metabolism; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D061251:Primary Cell Culture; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D047629:Estrogen Receptor beta; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D012322:RNA Precursors; D004958:Estradiol; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C447939:SIRT1 protein, human; D056564:Sirtuin 1
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