Gene expression profiling of prostate tissue identifies chromatin regulation as a potential link between obesity and lethal prostate cancer.

BACKGROUND: Obese men are at higher risk of advanced prostate cancer and cancer-specific mortality; however, the biology underlying this association remains unclear. This study examined gene expression profiles of prostate tissue to identify biological processes differentially expressed by obesity status and lethal prostate cancer. METHODS: Gene expression profiling was performed on tumor (n = 402) and adjacent normal (n = 200) prostate tissue from participants in 2 prospective cohorts who had been diagnosed with prostate cancer from 1982 to 2005. Body mass index (BMI) was calculated from the questionnaire immediately preceding cancer diagnosis. Men were followed for metastases or prostate cancer-specific death (lethal disease) through 2011. Gene Ontology biological processes differentially expressed by BMI were identified using gene set enrichment analysis. Pathway scores were computed by averaging the signal intensities of member genes. Odds ratios (ORs) for lethal prostate cancer were estimated with logistic regression. RESULTS: Among 402 men, 48% were healthy weight, 31% were overweight, and 21% were very overweight/obese. Fifteen gene sets were enriched in tumor tissue, but not normal tissue, of very overweight/obese men versus healthy-weight men; 5 of these were related to chromatin modification and remodeling (false-discovery rate < 0.25). Patients with high tumor expression of chromatin-related genes had worse clinical characteristics (Gleason grade > 7, 41% vs 17%; P = 2 × 10-4 ) and an increased risk of lethal disease that was independent of grade and stage (OR, 5.26; 95% confidence interval, 2.37-12.25). CONCLUSIONS: This study improves our understanding of the biology of aggressive prostate cancer and identifies a potential mechanistic link between obesity and prostate cancer death that warrants further study. Cancer 2017;123:4130-4138. © 2017 American Cancer Society.

The gut microbiome-prostate cancer crosstalk is modulated by dietary polyunsaturated long-chain fatty acids.

The gut microbiota modulates response to hormonal treatments in prostate cancer (PCa) patients, but whether it influences PCa progression remains unknown. Here, we show a reduction in fecal microbiota alpha-diversity correlating with increase tumour burden in two distinct groups of hormonotherapy naïve PCa patients and three murine PCa models. Fecal microbiota transplantation (FMT) from patients with high PCa volume is sufficient to stimulate the growth of mouse PCa revealing the existence of a gut microbiome-cancer crosstalk. Analysis of gut microbial-related pathways in mice with aggressive PCa identifies three enzymes responsible for the metabolism of long-chain fatty acids (LCFA). Supplementation with LCFA omega-3 MAG-EPA is sufficient to reduce PCa growth in mice and cancer up-grading in pre-prostatectomy PCa patients correlating with a reduction of gut Ruminococcaceae in both and fecal butyrate levels in PCa patients. This suggests that the beneficial effect of omega-3 rich diet is mediated in part by modulating the crosstalk between gut microbes and their metabolites in men with PCa.

Obesogenic High-Fat Diet and MYC Cooperate to Promote Lactate Accumulation and Tumor Microenvironment Remodeling in Prostate Cancer.

Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment (TME) and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet (HFD) rich in saturated fats accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic HFD was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages (TAM) and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In patients with prostate cancer, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like TAMs. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the TME and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer. SIGNIFICANCE: Lactate accumulation driven by high-fat diet and MYC reprograms the tumor microenvironment and promotes prostate cancer progression, supporting the potential of lactate as a biomarker and therapeutic target in prostate cancer. See related commentary by Frigo, p. 1742.

A two-stage, single-arm, phase II study of EGCG-enriched green tea drink as a maintenance therapy in women with advanced stage ovarian cancer.

OBJECTIVES: A two-stage, single-arm, phase II study was conducted to assess the effectiveness and safety of an epigallocatechin gallate (EGCG)-enriched tea drink, the double-brewed green tea (DBGT), as a maintenance treatment in women with advanced stage serous or endometrioid ovarian cancer (clinicaltrials.gov, NCT00721890). METHODS: Eligible women had FIGO stage III-IV serous or endometrioid ovarian cancer. They had to undergo complete response after debulking surgery followed by 6 to 8 cycles of platinum/taxane chemotherapy at the Centre Hospitalier Universitaire de Québec. They all had to drink the DBGT, 500 mL daily until recurrence or during a follow-up of 18 months. The primary endpoint was the absence of recurrence at 18 months. Statistical analyses were done according to the principle of intention to treat. Using a two-stage design, the first stage consisted of 16 enrolled patients. At the end of the follow-up, if 7 or fewer patients were free of recurrence, the trial stopped. Otherwise, accrual would continue to a total of 46 patients. RESULTS: During the first stage of the study, only 5 of the 16 women remained free of recurrence 18 months after complete response. Accordingly, the clinical trial was terminated. Women's adherence to DBGT was high (median daily intake during intervention, 98.1%, interquartile range: 89.7-100%), but 6 women discontinued the intervention before the end of their follow-up. No severe toxicity was reported. CONCLUSIONS: DBGT supplementation does not appear to be a promising maintenance intervention in women with advanced stage ovarian cancer after standard treatment.

SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation.

SOCS1 deficiency, which increases susceptibility to hepatocellular carcinoma (HCC), promotes CDKN1A expression in the liver. High CDKN1A expression correlates with disease severity in many cancers. Here, we demonstrate a crucial pathogenic role of CDKN1A in diethyl nitrosamine (DEN)-induced HCC in SOCS1-deficient mice. Mechanistic studies on DEN-induced genotoxic response revealed that SOCS1-deficient hepatocytes upregulate SOCS3 expression, SOCS3 promotes p53 activation, and Cdkn1a induction that were abolished by deleting either Socs3 or Tp53. Previous reports implicate CDKN1A in promoting oxidative stress response mediated by NRF2, which is required for DEN-induced hepatocarcinogenesis. We show increased induction of NRF2 and its target genes in SOCS1-deficient livers following DEN treatment that was abrogated by the deletion of either Cdkn1a or Socs3. Loss of SOCS3 in SOCS1-deficient mice reduced the growth of DEN-induced HCC without affecting tumor incidence. In the TCGA-LIHC dataset, the SOCS1-low/SOCS3-high subgroup displayed increased CDKN1A expression, enrichment of NRF2 transcriptional signature, faster disease progression, and poor prognosis. Overall, our findings show that SOCS1 deficiency in hepatocytes promotes compensatory SOCS3 expression, p53 activation, CDKN1A induction, and NRF2 activation, which can facilitate cellular adaptation to oxidative stress and promote neoplastic growth. Thus, the NRF2 pathway represents a potential therapeutic target in SOCS1-low/SOCS3-high HCC cases.

CdGAP is a talin-binding protein and a target of TGF-ß signaling that promotes HER2-positive breast cancer growth and metastasis.

Epithelial-to-mesenchymal transition (EMT) plays a crucial role in metastasis, which is the leading cause of death in breast cancer patients. Here, we show that Cdc42 GTPase-activating protein (CdGAP) promotes tumor formation and metastasis to lungs in the HER2-positive (HER2+) murine breast cancer model. CdGAP facilitates intravasation, extravasation, and growth at metastatic sites. CdGAP depletion in HER2+ murine primary tumors mediates crosstalk with a Dlc1-RhoA pathway and is associated with a transforming growth factor ß (TGF-ß)-induced EMT transcriptional signature. CdGAP is positively regulated by TGF-ß signaling during EMT and interacts with the adaptor talin to modulate focal adhesion dynamics and integrin activation. Moreover, HER2+ breast cancer patients with high CdGAP mRNA expression combined with a high TGF-ß-EMT signature are more likely to present lymph node invasion. Our results suggest CdGAP as a candidate therapeutic target for HER2+ metastatic breast cancer by inhibiting TGF-ß and integrin/talin signaling pathways.

Thermoneutrality and severe malaria: investigating the effect of warmer environmental temperatures on the inflammatory response and disease progression.

Introduction: Most studies using murine disease models are conducted at housing temperatures (20 - 22°C) that are sub-optimal (ST) for mice, eliciting changes in metabolism and response to disease. Experiments performed at a thermoneutral temperature (TT; 28 - 31°C) have revealed an altered immune response to pathogens and experimental treatments in murine disease model that have implications for their translation to clinical research. How such conditions affect the inflammatory response to infection with Plasmodium berghei ANKA (PbA) and disease progression is unknown. We hypothesized that changes in environmental temperature modulate immune cells and modify host response to malaria disease. To test this hypothesis, we conducted experiments to determine: (1) the inflammatory response to malarial agents injection in a peritonitis model and (2) disease progression in PbA-infected mice at TT compared to ST. Methods: In one study, acclimatized mice were injected intraperitoneally with native hemozoin (nHZ) or Leishmania at TT (28 - 31°C) or ST, and immune cells, cytokine, and extracellular vesicle (EV) profiles were determined from the peritoneal cavity (PEC) fluid. In another study, PbA-infected mice were monitored until end-point (i.e. experimental malaria score ≥4). Results: We found that Leishmania injection resulted in decreased cell recruitment and higher phagocytosis of nHZ in mice housed at TT. We found 398 upregulated and 293 downregulated proinflammatory genes in mice injected with nHZ, at both temperatures. We report the presence of host-derived EVs never reported before in a murine parasitic murine model at both temperatures. We observed metabolic changes in mice housed at TT, but these did not result to noticeable changes in disease progression compared to ST. Discussion: To our knowledge, these experiments are the first to investigate the effect of thermoneutrality on a malaria murine model. We found important metabolic difference in mice housed at TT. Our results offer insights on how thermoneutrality might impact a severe malaria murine model and directions for more targeted investigations.

Green tea for ovarian cancer prevention and treatment: a systematic review of the in vitro, in vivo and epidemiological studies.

OBJECTIVE: This systematic review was conducted to examine the effects of green tea or green tea components on the prevention and progression of epithelial ovarian cancer. METHODS: Using Medline, EMBASE and SciVerse (last researched: July 2011), we retrieved 22 articles including 5 epidemiological studies. RESULTS: In epithelial ovarian cancer cell lines, green tea and green tea components have been shown to downregulate the expression of proteins involved in inflammation, cell signalization, cell motility and angiogenesis. Green tea and green tea components would induce apoptosis and could potentiate the effects of cisplatin, a chemotherapeutic agent. In human observational studies, significant associations between green tea intake and both decreased ovarian cancer occurrence and better prognosis were reported. CONCLUSIONS: Available literature suggests potential molecular targets for green tea in ovarian cancer treatment and also provides data supporting the clinical evaluation of the role of green tea or green tea components in ovarian cancer prevention and treatment.

The Extracellular Matrix Stiffening: A Trigger of Prostate Cancer Progression and Castration Resistance?

Despite advancements made in diagnosis and treatment, prostate cancer remains the second most diagnosed cancer among men worldwide in 2020, and the first in North America and Europe. Patients with localized disease usually respond well to first-line treatments, however, up to 30% develop castration-resistant prostate cancer (CRPC), which is often metastatic, making this stage of the disease incurable and ultimately fatal. Over the last years, interest has grown into the extracellular matrix (ECM) stiffening as an important mediator of diseases, including cancers. While this process is increasingly well-characterized in breast cancer, a similar in-depth look at ECM stiffening remains lacking for prostate cancer. In this review, we scrutinize the current state of literature regarding ECM stiffening in prostate cancer and its potential association with disease progression and castration resistance.

To bind or not to bind: Cistromic reprogramming in prostate cancer.

The term "cistrome" refers to the genome-wide location of regulatory elements associated with transcription factor binding-sites. The cistrome of key regulatory factors in prostate cancer etiology are substantially reprogrammed and altered during prostatic transformation and disease progression. For instance, the cistrome of the androgen receptor (AR), a ligand-inducible transcription factor central in normal prostate epithelium biology, is directly impacted and substantially reprogrammed during malignant transformation. Accumulating evidence demonstrates that additional transcription factors that are frequently mutated, or aberrantly expressed in prostate cancer, such as the pioneer transcription factors Forkhead Box A1 (FOXA1), the homeobox protein HOXB13, and the GATA binding protein 2 (GATA2), and the ETS-related gene (ERG), and the MYC proto-oncogene, contribute to the reprogramming of the AR cistrome. In addition, recent findings have highlighted key roles for the SWI/SNF complex and the chromatin-modifying helicase CHD1 in remodeling the epigenome and altering the AR cistrome during disease progression. In this review, we will cover the role of cistromic reprogramming in prostate cancer initiation and progression. Specifically, we will discuss the impact of key prostate cancer regulators, as well as the role of epigenetic and chromatin regulators in relation to the AR cistrome and the transformation of normal prostate epithelium. Given the importance of chromatin-transcription factor dynamics in normal cellular differentiation and cancer, an in-depth assessment of the factors involved in producing these altered cistromes is of great relevance and provides insight into new therapeutic strategies for prostate cancer.

Protein tyrosine phosphatase 1B regulates miR-208b-argonaute 2 association and thyroid hormone responsiveness in cardiac hypertrophy.

Increased production of reactive oxygen species plays an essential role in the pathogenesis of several diseases, including cardiac hypertrophy. In our search to identify redox-sensitive targets that contribute to redox signaling, we found that protein tyrosine phosphatase 1B (PTP1B) was reversibly oxidized and inactivated in hearts undergoing hypertrophy. Cardiomyocyte-specific deletion of PTP1B in mice (PTP1B cKO mice) caused a hypertrophic phenotype that was exacerbated by pressure overload. Furthermore, we showed that argonaute 2 (AGO2), a key component of the RNA-induced silencing complex, was a substrate of PTP1B in cardiomyocytes and in the heart. Our results revealed that phosphorylation at Tyr393 and inactivation of AGO2 in PTP1B cKO mice prevented miR-208b-mediated repression of thyroid hormone receptor-associated protein 1 (THRAP1; also known as MED13) and contributed to thyroid hormone-mediated cardiac hypertrophy. In support of this conclusion, inhibiting the synthesis of triiodothyronine (T3) with propylthiouracil rescued pressure overload-induced hypertrophy and improved myocardial contractility and systolic function in PTP1B cKO mice. Together, our data illustrate that PTP1B activity is cardioprotective and that redox signaling is linked to thyroid hormone responsiveness and microRNA-mediated gene silencing in pathological hypertrophy.

Response to supraphysiological testosterone is predicted by a distinct androgen receptor cistrome.

The androgen receptor (AR) is a master transcription factor that regulates prostate cancer (PC) development and progression. Inhibition of AR signaling by androgen deprivation is the first-line therapy with initial efficacy for advanced and recurrent PC. Paradoxically, supraphysiological levels of testosterone (SPT) also inhibit PC progression. However, as with any therapy, not all patients show a therapeutic benefit, and responses differ widely in magnitude and duration. In this study, we evaluated whether differences in the AR cistrome before treatment can distinguish between SPT-responding (R) and -nonresponding (NR) tumors. We provide the first preclinical evidence to our knowledge that SPT-R tumors exhibit a distinct AR cistrome when compared with SPT-NR tumors, indicating a differential biological role of the AR. We applied an integrated analysis of ChIP-Seq and RNA-Seq to the pretreatment tumors and identified an SPT-R signature that distinguishes R and NR tumors. Because transcriptomes of SPT-treated clinical specimens are not available, we interrogated available castration-resistant PC (CRPC) transcriptomes and showed that the SPT-R signature is associated with improved survival and has the potential to identify patients who would respond to SPT. These findings provide an opportunity to identify the subset of patients with CRPC who would benefit from SPT therapy.

MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets.

c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Analyses of clinical specimens reveal that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq uncover an increase in RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.

Diet-Dependent Metabolic Regulation of DNA Double-Strand Break Repair in Cancer: More Choices on the Menu.

Despite several epidemiologic and preclinical studies supporting the role of diet in cancer progression, the complexity of the diet-cancer link makes it challenging to deconvolute the underlying mechanisms, which remain scantly elucidated. This review focuses on genomic instability as one of the cancer hallmarks affected by diet-dependent metabolic alterations. We discuss how altered dietary intake of metabolites of the one-carbon metabolism, including methionine, folate, and vitamins B and C, can impact the methylation processes and thereby tumorigenesis. We present the concept that the protumorigenic effect of certain diets, such as the Western diet, is in part due to a diet-induced erosion of the DNA repair capacity caused by altered epigenetic and epitranscriptomic landscapes, while the protective effect of other dietary patterns, such as the Mediterranean diet, can be partly explained by their ability to sustain a proficient DNA repair. In particular, considering that diet-dependent alterations of the one-carbon metabolism can impact the rate of methylation processes, changes in dietary patterns can affect the activity of writers and erasers of histone and RNA methyl marks and consequently impair their role in ensuring a proficient DNA damage repair.

CdGAP promotes prostate cancer metastasis by regulating epithelial-to-mesenchymal transition, cell cycle progression, and apoptosis.

High mortality of prostate cancer patients is primarily due to metastasis. Understanding the mechanisms controlling metastatic processes remains essential to develop novel therapies designed to prevent the progression from localized disease to metastasis. CdGAP plays important roles in the control of cell adhesion, migration, and proliferation, which are central to cancer progression. Here we show that elevated CdGAP expression is associated with early biochemical recurrence and bone metastasis in prostate cancer patients. Knockdown of CdGAP in metastatic castration-resistant prostate cancer (CRPC) PC-3 and 22Rv1 cells reduces cell motility, invasion, and proliferation while inducing apoptosis in CdGAP-depleted PC-3 cells. Conversely, overexpression of CdGAP in DU-145, 22Rv1, and LNCaP cells increases cell migration and invasion. Using global gene expression approaches, we found that CdGAP regulates the expression of genes involved in epithelial-to-mesenchymal transition, apoptosis and cell cycle progression. Subcutaneous injection of CdGAP-depleted PC-3 cells into mice shows a delayed tumor initiation and attenuated tumor growth. Orthotopic injection of CdGAP-depleted PC-3 cells reduces distant metastasic burden. Collectively, these findings support a pro-oncogenic role of CdGAP in prostate tumorigenesis and unveil CdGAP as a potential biomarker and target for prostate cancer treatments.

EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer.

Prostate cancers are considered to be immunologically 'cold' tumors given the very few patients who respond to checkpoint inhibitor (CPI) therapy. Recently, enrichment of interferon-stimulated genes (ISGs) predicted a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is overexpressed in prostate cancer and known to negatively regulate ISGs. In the present study, we demonstrate that EZH2 inhibition in prostate cancer models activates a double-stranded RNA-STING-ISG stress response upregulating genes involved in antigen presentation, Th1 chemokine signaling and interferon response, including programmed cell death protein 1 (PD-L1) that is dependent on STING activation. EZH2 inhibition substantially increased intratumoral trafficking of activated CD8+ T cells and increased M1 tumor-associated macrophages, overall reversing resistance to PD-1 CPI. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. These data suggest EZH2 inhibition as a therapeutic direction to enhance prostate cancer response to PD-1 CPI.

Evidence that EZH2 Deregulation is an Actionable Therapeutic Target for Prevention of Prostate Cancer.

Chemoprevention trials for prostate cancer by androgen receptor or androgen synthesis inhibition have proven ineffective. Recently, it has been demonstrated that the histone methlytransferase, EZH2 is deregulated in mouse and human high-grade prostatic intraepithelial neoplasia (HG-PIN). Using preclinical mouse and human models of prostate cancer, we demonstrate that genetic and chemical disruption of EZH2 expression and catalytic activity reversed the HG-PIN phenotype. Furthermore, inhibition of EZH2 function was associated with loss of cellular proliferation and induction of Tp53-dependent senescence. Together, these data provide provocative evidence for EZH2 as an actionable therapeutic target toward prevention of prostate cancer.

Proteases and their inhibitors as prognostic factors for high-grade serous ovarian cancer.

Ovarian carcinoma is one of the most lethal malignancies, but only very few prognostic biomarkers are known. The degradome, comprising proteases, protease non-proteolytic homologues and inhibitors, have been involved in the prognosis of many cancer types, including ovarian carcinoma. The prognostic significance of the whole degradome family has not been specifically studied in high-grade serous ovarian cancer. A targeted DNA microarray known as the CLIP-CHIP microarray was used to identify potential prognostic factors in ten high-grade serous ovarian cancer women who had early recurrence (<1.6 years) or late/no recurrence after first line surgery and chemotherapy. In women with early recurrence, we identified seven upregulated genes (TMPRSS4, MASP1/3, SPC18, PSMB1, IGFBP2, CFI - encoding Complement Factor I - and MMP9) and one down-regulated gene (ADAM-10). Using immunohistochemistry, we evaluated the prognostic effect of these 8 candidate genes in an independent cohort of 112 high-grade serous ovarian cancer women. Outcomes were progression, defined according to CA-125 criteria, and death. Multivariate Cox proportional hazard regression models were done to estimate the associations between each protein and each outcome. High ADAM-10 expression (intensity of 2-3) was associated with a lower risk of progression (adjusted hazard ratio (HR): 0.51; 95% confidence interval (CI): 0.29-0.87). High complement factor I expression (intensity 2-3) was associated with a higher risk of progression (adjusted HR: 2.30, 95% CI: 1.17-4.53) and death (adjusted HR: 3.42; 95% CI: 1.72-6.79). Overall, we identified the prognostic value of two proteases, ADAM-10 and complement factor I, for high-grade serous ovarian cancer which could have clinical significance.

High-fat diet fuels prostate cancer progression by rewiring the metabolome and amplifying the MYC program.

Systemic metabolic alterations associated with increased consumption of saturated fat and obesity are linked with increased risk of prostate cancer progression and mortality, but the molecular underpinnings of this association are poorly understood. Here, we demonstrate in a murine prostate cancer model, that high-fat diet (HFD) enhances the MYC transcriptional program through metabolic alterations that favour histone H4K20 hypomethylation at the promoter regions of MYC regulated genes, leading to increased cellular proliferation and tumour burden. Saturated fat intake (SFI) is also associated with an enhanced MYC transcriptional signature in prostate cancer patients. The SFI-induced MYC signature independently predicts prostate cancer progression and death. Finally, switching from a high-fat to a low-fat diet, attenuates the MYC transcriptional program in mice. Our findings suggest that in primary prostate cancer, dietary SFI contributes to tumour progression by mimicking MYC over expression, setting the stage for therapeutic approaches involving changes to the diet.

Transcriptional Regulation in Prostate Cancer.

Prostate cancer development involves corruption of the normal prostate transcriptional network, following deregulated expression or mutation of key transcription factors. Here, we provide an overview of the transcription factors that are important in normal prostate homeostasis (NKX3-1, p63, androgen receptor [AR]), primary prostate cancer (ETS family members, c-MYC), castration-resistant prostate cancer (AR, FOXA1), and AR-independent castration-resistant neuroendocrine prostate cancer (RB1, p53, N-MYC). We use functional (in vitro and in vivo) as well as clinical data to discuss evidence that unveils their roles in the initiation and progression of prostate cancer, with an emphasis on results of chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq).