Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit distinct metabolomes and nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish the mitochondrial pyruvate carrier and subsequent lactate accumulation as regulators of prostate luminal identity. Inhibition of the mitochondrial pyruvate carrier or supplementation with exogenous lactate results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors and response to antiandrogen treatment. These results establish reciprocal regulation of metabolism and prostate epithelial lineage identity. 

Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment

The antiproliferative properties of metformin and silodosin have been observed in prostate cancer. Furthermore, it is hypothesized that the molecular pathways related to these drugs may impact the levels of human telomerase reverse transcriptase (hTERT) in prostate cancer cells. The aim of this study was to assess the effect of metformin and silodosin on the levels of hTERT in metastatic castration-resistant prostate cancer (mCRPC) cells. The present study employed an experimental design with a post-test-only control group.  This study utilized the PC3 cell line as a model for mCRPC. A viability experiment was conducted using the CCK-8 method to determine the inhibitory concentration (IC50) values of metformin, silodosin, and abiraterone acetate (AA) after a 72-hour incubation period of PC3 cells. In order to investigate the levels of hTERT, PC3 cells were divided into two control groups: a negative control and a standard therapy with AA. Additionally, three experimental combination groups were added: metformin with AA; silodosin with AA; and metformin, silodosin and AA. The level of hTERT was measured using sandwich ELISA technique. The difference in hTERT levels was assessed using ANOVA followed by a post hoc test. The IC50 values for metformin, silodosin, and AA were 17.7 mM, 44.162 mM, and 66.9 μM, respectively. Our data indicated that the combination of metformin with AA and the combination of metformin, silodosin and AA decreased the hTERT levels when compared to control, AA, and silodosin with AA. The administration of metformin resulted in a reduction of hTERT levels in the PC3 cell line, but the impact of silodosin on hTERT levels was not statistically significant compared to AA group.

Effects of metformin and silodosin as supplementary treatments to abiraterone on human telomerase reverse transcriptase (hTERT) level in metastatic castration-resistant prostate cancer (mCRPC) cells: An in vitro study

The telomere repetitive TTAGGG motif at the ends of chromosomes, serves to preserve genomic integrity and chromosomal stability. In turn, genomic instability is a hallmark of cancer-implicating telomere disturbance. Prostate cancer (PCa) shows significant ancestral disparities, with men of African ancestry at the greatest risk for aggressive disease and associated genomic instability. Yet, no study has explored the role of telomere length (TL) with respect to ancestrally driven PCa health disparities. Patient- and technically-matched tumour-blood whole genome sequencing data for 179 ancestrally defined treatment naïve PCa patients (117 African, 62 European), we assessed for TL (blood and tumour) associations. We found shortened tumour TL to be associated with aggressive PCa presentation and elevated genomic instabilities, including percentage of genome alteration and copy number gains, in men of African ancestry. For European patients, tumour TL showed significant associations with PCa driver genes PTEN, TP53, MSH2, SETBP1 and DDX11L1, while shorter blood TL (< 3200 base pairs) and tumour TL (< 2861 base pairs) were correlated with higher risk for biochemical recurrence. Concurring with previous studies linking TL to PCa diagnosis and/or prognosis, for the first time we correlated TL differences with patient ancestry with important implications for future treatments targeting telomere dysfunction. 

The impact of telomere length on prostate cancer aggressiveness, genomic instability and health disparities

Simple Summary Telomeres are essential to prevent telomere end fusions that cause the formation of dicentric chromosomes and nucleoplasmic bridges (NPBs) which in turn induce chromosomal instability, cancer initiation and progression. In this study, we show that telomere length (TL) is reduced and NPBs are increased in prostate cancer (PC) cases and the incidence of these adverse genomic insults is further elevated with increased severity of disease. NPBs and TL in white blood cells may have clinical utility to identify and triage PC cases who may be at risk of serious disease. More studies are required to confirm our observations and to explore mechanistic differences in the role of telomeres in NPB formation in PC cases relative to healthy controls. Abstract Telomeres are repetitive nucleotide (TTAGGG) sequences that stabilize the chromosome ends and play an important role in the prevention of cancer initiation and progression. Nucleoplasmic bridges (NPBs) are formed when chromatids remain joined together during mitotic anaphase either due to mis-repair of DNA breaks or due to chromatid end fusion as a result of telomere loss or telomere dysfunction. We tested the hypotheses that (i) telomere length (TL) is shorter in prostate cancer (PC) patients relative to healthy age-matched individuals, (ii) TL differs in different stages of PC and (iii) shorter TL is significantly correlated with NPBs formation in PC cases. TL was measured in whole blood by well-established quantitative PCR method and the frequency of NPBs was measured in lymphocytes using cytokinesis-block micronucleus cytome (CBMNcyt) assay. Our results indicate that TL is shorter and NPBs are increased in PC patients relative to age-matched healthy controls. Furthermore, TL was significantly shorter (p = 0.03) in patients with a Gleason score more than 7 and there was also a significant trend of decreasing TL across all three stages (p trend = 0.01; Gleason score <7, 7 and >7). Furthermore, TL was significantly inversely correlated with NPB frequency in PC patients (r = −0.316; p = 0.001) but not in controls (r = 0.163; p = 0.06) and their relationships became stronger with higher Gleason scores. More studies are required that can confirm our observations and explore mechanistic differences in the role of telomeres in NPB formation in PC cases relative to non-cancer cases.

/pdf/the-relationship-between-telomere-length-and-nucleoplasmic-28agmmvg.pdf

The Relationship between Telomere Length and Nucleoplasmic Bridges and Severity of Disease in Prostate Cancer Patients

Abstract Background Telomere-related genes (TRGs) play an essential role in the carcinogenesis and progression of prostate adenocarcinoma(PRAD). However, the prognostic value of TRGs remains unclear in PRAD. Methods We conducted a study using The Cancer Genome Atlas-Prostate Adenocarcinoma (TCGA-PRAD) dataset as the training group and the Memorial Sloan-Kettering Cancer Center (MSKCC) and Gene Expression Omnibus (GEO) datasets as the validation group. We developed a risk model and a nomogram to predict survival rates in patients with PRAD. The expression of model genes and their possible regulatory mechanisms were then analyzed. Furthermore, we explored the relationship between the risk model and immune cell infiltration, chemotherapy drug sensitivity, and specific signaling pathways using the CIBERSORT algorithm, the Genomics of Drug Sensitivity in Cancer (GDSC) database, and motif enrichment. Results The developed risk model was based on seven key TRGs ( HELLS , TOP3A , SRC , LARP7 , BUB3 , THRSP , and GTF2H4 ). Moreover, this model was an independent prognostic factor for patients with PRAD and was significantly associated with T and N stages. Among seven TRGs, TOP3A and BUB3 were not only significantly positively correlated with the clinical T and N phases of PRAD, but also expression was significantly increased in PRAD tissues compared to adjacent normal tissues. The model was a good predictor of 1-, 3-, and 5-year survival, and patients in the high-risk group had significantly shorter overall survival than those in the low-risk group. The integrated nomogram can be a good predictor of 3- and 5-year survival in patients with PRAD. Finally, compared to the low-risk group, the high-risk group had a higher response to chemotherapy and immunosuppression, which provided potential guidance to treatment options for patients in the high-risk group. Conclusion In summary, a new risk model based on TRGs was successfully developed in PRAD. This risk model is valuable for guiding the selection of immunotherapy and chemotherapy in the clinical treatment of patients with PRAD. 

Predicting Prostate Adenocarcinoma Patients’ Survival and Immune Signature: A Novel Risk Model Based on Telomere-Related Genes

Replicative immortality is a hallmark of cancer, and can be achieved through telomere lengthening and maintenance. Although the role of telomere length in cancer has been well studied, its association to genomic features is less well known. Here, we report the telomere lengths of 392 localized prostate cancer tumours and characterize their relationship to genomic, transcriptomic and proteomic features. Shorter tumour telomere lengths are associated with elevated genomic instability, including single-nucleotide variants, indels and structural variants. Genes involved in cell proliferation and signaling are correlated with tumour telomere length at all levels of the central dogma. Telomere length is also associated with multiple clinical features of a tumour. Longer telomere lengths in non-tumour samples are associated with a lower rate of biochemical relapse. In summary, we describe the multi-level integration of telomere length, genomics, transcriptomics and proteomics in localized prostate cancer.

The telomere length landscape of prostate cancer.

Replicative immortality is a hallmark of cancer, and can be achieved through telomere lengthening and maintenance. We report telomere lengths (TLs) of 392 localized prostate cancer tumours and characterize their relationship to genomic, transcriptomic and proteomic features. Shorter tumour TLs were associated with elevated genomic instability, including single-nucleotide variants, indels and structural variants. Genes involved in cell proliferation and signaling were correlated with tumour TL at all levels of the central dogma. TL was also associated with multiple clinical features of a tumour. Longer TLs in non-tumour (blood) samples were associated with a lower rate of biochemical relapse after definitive local therapy. Our analysis integrates multi-omics data to illuminate the relationship of specific genomic alterations in a tumour and TL in prostate cancer. Although the role of telomere length in cancer has been well studied, its association to genomic features is less well known. We describe the multi-level integration of telomere length, genomics, transcriptomics and proteomics in localized prostate cancer. Patient Summary: We examined the association between telomere length and multiple omics-level data in prostate cancer. We observed that traditional telomere mutations are rare in prostate cancer and that telomere length is associated with multiple measure of genomic instability.

/pdf/the-telomere-length-landscape-of-prostate-cancer-1idr37pf1k.pdf

The Telomere Length Landscape of Prostate Cancer

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The telomere length landscape of prostate cancer.

The Telomere Length Landscape of Prostate Cancer