CTBP1/CYP19A1/estradiol axis together with adipose tissue impacts over prostate cancer growth associated to metabolic syndrome

Abstract

Metabolic syndrome (MeS) increases prostate cancer (PCa) risk and aggressiveness. C-terminal binding protein 1 (CTBP1) is a transcriptional co-repressor of tumor suppressor genes that is activated by low NAD /NADH ratio. Previously, our group established a MeS and PCa mice model that identified CTBP1 as a novel link associating both diseases. We found that CTBP1 controls the transcription of aromatase (CYP19A1), a key enzyme that converts androgens to estrogens. The aim of this work was to investigate the mechanism that explains CTBP1 as a link between MeS and PCa based on CYP19A1 and estrogen synthesis regulation using PCa cell lines, MeS/PCa mice and adipose co-culture systems. We found that CTBP1 and E1A binding protein p300 (EP300) bind to CYP19A1 promoter and downregulate its expression in PC3 cells. Estradiol, through estrogen receptor beta, released CTBP1 from CYP19A1 promoter triggering its transcription and modulating PCa cell proliferation. We generated NSG and C57BL/6J MeS mice by chronically feeding animals with high fat diet. In the NSG model, CTBP1 depleted PCa xenografts showed an increase in CYP19A1 expression with subsequent increment in intratumor estradiol concentrations. Additionally, in C57BL/6J mice, MeS induced hypertrophy, hyperplasia and inflammation of the white adipose tissue, which leads to a proinflammatory phenotype and increased serum estradiol concentration. Thus, MeS increased PCa growth and Ctbp1, Fabp4 and IL-6 expression levels. These results describe, for the first time, a novel CTBP1/CYP19A1/Estradiol axis that explains, in part, the mechanism for prostate tumor growth increase by MeS.

Research Evidence on High-Fat Diet-Induced Prostate Cancer Development and Progression

“…Given the variations in the genetic background of mouse strains, it is important to consider the importance of the immune system in tumor progression [59]. Several studies have investigated the impact of dietary fat on allografts using immunocompetent mice and mouse-derived prostate cancer cells [31,41,45,49,55]. Several groups have shown that a HFD significantly increased allograft tumor growth of TRAMP-derived prostate cancer cells, such as TRAMP-C1 and TRAMP-C2, in C57BL6 mice [31,41,55].…”

“…Several studies have investigated the impact of dietary fat on allografts using immunocompetent mice and mouse-derived prostate cancer cells [31,41,45,49,55]. Several groups have shown that a HFD significantly increased allograft tumor growth of TRAMP-derived prostate cancer cells, such as TRAMP-C1 and TRAMP-C2, in C57BL6 mice [31,41,55]. The study involving the largest number of allografts (low-fat; n = 40, high-fat; n = 134) revealed that mice receiving AIN-93M-high-fat diet had significantly heavier and significantly larger TRAMP-C2 allografts compared to those receiving AIN-93M, whereas no differences in prostate weight were observed among the groups [31].…”

“…These results suggest that fat-containing diets, especially those that modulate of omega-3 fatty acid content, may potentially modulate intraprostatic hormonal status associated with cancerous tumor growth and progression. In the TRAMP-C1 allograft study, HFD increased tumor growth and serum estradiol levels [55]. The study also showed that intratumoral C-terminal-binding protein 1 (CtBP1) controls the transcription of aromatase (CYP19A), a key enzyme that converts androgens to estrogens, and was overexpressed with increased TRAMP-C1 allograft tumor growth in mice receiving a HFD.…”

Adipose tissue from metabolic syndrome mice induces an aberrant miRNA signature highly relevant in prostate cancer development

“…Thus, we identified novel pathways regulated by CTBP1 on a MeS environment [4,5]. CTBP1 depletion in androgeninsensitive PCa xenografts from HFD-fed mice affects the expression of genes and microRNAs (miRNAs) involved in hormone biosynthesis, olfactory signaling, and cell adhesion pathways, impacting in PCa development and progression [6][7][8]. Additionally, an androgen-sensitive PCa and MeS-like mice model allowed us to determine that MeS significantly increased tumor growth.…”

“…Compared to control diet (CD), HFD-fed mice showed high amount of white adipose tissue (WAT), adipocyte size, and macrophage infiltration, with adipogenesis and inflammation-related genes expression induction, which indicates chronic WAT inflammation, an important feature of MeS. Additionally, cocultures of androgen-sensitive PCa cells with WAT determined that WAT from HFD-fed mice induced proliferation and expression of oncogenes in PCa cells [7]. miRNAs are small noncoding RNAs (18-22 nts long) that target mRNA to reduce protein expression [9].…”