Endothelial NOS, estrogen receptor beta, and HIFs cooperate in the activation of a prognostic transcriptional pattern in aggressive human prostate cancer.
The identification of biomarkers that distinguish between aggressive and indolent forms of prostate cancer (PCa) is crucial for diagnosis and treatment. In this study, we used cultured cells derived from prostate tissue from patients with PCa to define a molecular mechanism underlying the most aggressive form of PCa that involves the functional activation of eNOS and HIFs in association with estrogen receptor beta (ERbeta). Cells from patients with poor prognosis exhibited a constitutively hypoxic phenotype and increased NO production. Upon estrogen treatment, formation of ERbeta/eNOS, ERbeta/HIF-1alpha, or ERbeta/HIF-2alpha combinatorial complexes led to chromatin remodeling and transcriptional induction of prognostic genes. Tissue microarray analysis, using an independent cohort of patients, established a hierarchical predictive power for these proteins, with expression of eNOS plus ERbeta and nuclear eNOS plus HIF-2alpha being the most relevant indicators of adverse clinical outcome. Genetic or pharmacologic modulation of eNOS expression and activity resulted in reciprocal conversion of the transcriptional signature in cells from patients with bad or good outcome, respectively, highlighting the relevance of eNOS in PCa progression. Our work has considerable clinical relevance, since it may enable the earlier diagnosis of aggressive PCa through routine biopsy assessment of eNOS, ERbeta, and HIF-2alpha expression. Furthermore, proposing eNOS as a therapeutic target fosters innovative therapies for PCa with NO inhibitors, which are employed in preclinical trials in non-oncological diseases.
Nanni
Simona
S
Department of Experimental Oncology, Regina Elena Cancer Institute, Rome, Italy.
Benvenuti
Valentina
V
Grasselli
Annalisa
A
Priolo
Carmen
C
Aiello
Aurora
A
Mattiussi
Stefania
S
Colussi
Claudia
C
Lirangi
Vittoria
V
Illi
Barbara
B
D'Eletto
Manuela
M
Cianciulli
Anna Maria
AM
Gallucci
Michele
M
De Carli
Piero
P
Sentinelli
Steno
S
Mottolese
Marcella
M
Carlini
Paolo
P
Strigari
Lidia
L
Finn
Stephen
S
Mueller
Elke
E
Arcangeli
Giorgio
G
Gaetano
Carlo
C
Capogrossi
Maurizio C
MC
Donnorso
Raffaele Perrone
RP
Bacchetti
Silvia
S
Sacchi
Ada
A
Pontecorvi
Alfredo
A
Loda
Massimo
M
Farsetti
Antonella
A
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000502:physiology; D003593:Cytoplasm / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D051272:Glucose Transporter Type 1 / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D004791:Enzyme Inhibitors; D004958:Estradiol; D047629:Estrogen Receptor beta; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D052250:Nitric Oxide Synthase Type III; D019098:Telomerase; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C495677:SLC2A1 protein, human; C467484:VEGFA protein, human; C496314:NOS3 protein, human; C509186:TERT protein, human