CtBP1 functions as a switch to control AROMATASE transcription in response to the metabolic status of the prostate cancer cells.

MASSILLO CL; DALTON N; PORRETTI J; DE LUCA P; DE SIERVI A

Mar del Plata

Congreso; LXI Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica; 2016

Sociedad Argentina de Investigación Clínica

The normal growth and development of the prostate requires the action of estrogens and estrogens receptors (ER) α and β. Estrogenrelated pathways are clearly important in the development and progression of hormonedependentcancers such as prostate cancer (PCa), but the role of ERβ remains controversial. The prostate cancer (PCa), but the role of ERβ remains controversial. The production of estrogens from androgens is mediated by the aromatase enzyme. Aberrant expression of aromatase plays a critical role in PCa development and progression. Metabolic syndrome (MeS) causes sexhormone imbalance and has been identified as a risk factor for PCa. Recently, we found that C terminal binding protein (CtBP1), a transcriptional corepressorof tumor suppressor genes, is a novel molecular link between MeS and PCa. Wedeveloped a MeS mice model that were inoculated with PC3 stable CtBP1 depleted or control cells. MeS mice showed hormone imbalance and high levels of intratumor estradiol. Interestingly, CtBP1 strongly repressed aromatase expression in these xenografts. The aim of this study was to understand the transcriptional regulation mechanism of aromatase mediated by CtBP1 in a MeS/PCa model. By chromatin immunoprecipitation (ChIP), we determined that CtBP1, p300 and ERβ associate to aromatase promoter in PC3 cells. Using gene reporter assays, we found that CtBP1 and p300 synergistically repress, while ER β activates, aromatase promoter activity. Interestingly, estradiol exposure of PC3 cells, released CtBP1 from the aromatase promoter triggering its expression. Furthermore, we found that estradiol dramatically increased the viability of the LNCaP cells and its derivative C42, both sensitive to androgens. However, estradiol induced G1 phase arrest in androgen insensitive PC3 cells. In summary, CtBP1 represses aromatase expression en PCa. Nevertheless MeS induces estradiol, releases CtBP1 and activates aromatase expression, which in turn, increases prostate tumor cell proliferation in androgen sensitive cells.