Prostate cancer bone metastases biology and clinical management (Review)

Prostate cancer (PCa) is one of the most prominent causes of cancer‑related mortality in the male population. A highly impactful prognostic factor for patients diagnosed with PCa is the presence or absence of bone metastases. The forma‑ tion of secondary tumours at the bone is the most commonly observed site for the establishment of PCa metastases and is associated with reduced survival of patients in addition to a cohort of life‑debilitating symptoms, including mobility issues and chronic pain. Despite the prevalence of this disease presen‑ tation and the high medical relevance of bone metastases, the mechanisms underlying the formation of metastases to the bone and the understanding of what drives the osteotropism exhibited by prostate tumours remain to be fully elucidated. This lack of in‑depth understanding manifests in limited effec‑ tive treatment options for patients with advanced metastatic PCa and culminates in the low rate of survival observed for this sub‑set of patients. The present review aims to summarise the most recent promising advances in the understanding of how and why prostate tumours metastasise to the bone, with the ultimate aim of highlighting novel treatment and prog‑ nostic targets, which may provide the opportunity to improve the diagnosis and treatment of patients with PCa with bone metastases

Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer

Prostate is the most frequent cancer in men. Prostate cancer progression is driven by androgen steroid hormones, and delayed by androgen deprivation therapy (ADT). Androgens control transcription by stimulating androgen receptor (AR) activity, yet also control pre-mRNA splicing through less clear mechanisms. Here we find androgens regulate splicing through AR-mediated transcriptional control of the epithelial-specific splicing regulator ESRP2. Both ESRP2 and its close paralog ESRP1 are highly expressed in primary prostate cancer. Androgen stimulation induces splicing switches in many endogenous ESRP2-controlled mRNA isoforms, including splicing switches correlating with disease progression. ESRP2 expression in clinical prostate cancer is repressed by ADT, which may thus inadvertently dampen epithelial splice programmes. Supporting this, treatment with the AR antagonist bicalutamide (Casodex) induced mesenchymal splicing patterns of genes including FLNB and CTNND1. Our data reveals a new mechanism of splicing control in prostate cancer with important implications for disease progression.This article is freely available via Open Access. Click on the Publisher URL to access the full-text via the publisher's site

Sialylation inhibition can partially revert acquired resistance to enzalutamide in prostate cancer cells

Prostate cancer is the most common cancer in men and a major cause of cancer-related deaths around the world. Prostate cancer that has spread to other parts of the body (advanced prostate cancer) is often treated with a drug called enzalutamide, which is a type of hormone therapy. Enzalutamide works by blocking the effect of the testosterone hormone on prostate cancer cells to stop them from growing. While this can be effective for several years, unfortunately, many patients being treated with enzalutamide eventually go on to become resistant to treatment, and the therapy stops working. Here, we show that prostate cancer cells that have become resistant to enzalutamide have increased levels of a type of sugar (known as sialic acid) on their surfaces. We set out to test whether stripping sialic acid from the surface of prostate cancer cells could help keep enzalutamide working for longer. Excitingly, our experiments show that treating prostate cancer cells with a drug to block sialic acid can partially reverse enzalutamide resistance. These findings suggest that drugs targeting sialic acid could be used in combination with enzalutamide therapy to disarm drug resistance and provide urgently needed new treatment options for men with prostate cancer

Targeting aberrant sialylation and fucosylation in prostate cancer cells using potent metabolic inhibitors

Aberrant glycosylation is a hallmark of cancer and is not just a consequence, but also a driver of a malignant phenotype. In prostate cancer, changes in fucosylated and sialylated glycans are common and this has important implications for tumor progression, metastasis, and immune evasion. Glycans hold huge translational potential and new therapies targeting tumor-associated glycans are currently being tested in clinical trials for several tumor types. Inhibitors targeting fucosylation and sialylation have been developed and show promise for cancer treatment, but translational development is hampered by safety issues related to systemic adverse effects. Recently, potent metabolic inhibitors of sialylation and fucosylation were designed that reach higher effective concentrations within the cell, thereby rendering them useful tools to study sialylation and fucosylation as potential candidates for therapeutic testing. Here, we investigated the effects of global metabolic inhibitors of fucosylation and sialylation in the context of prostate cancer progression. We find that these inhibitors effectively shut down the synthesis of sialylated and fucosylated glycans to remodel the prostate cancer glycome with only minor apparent side effects on other glycan types. Our results demonstrate that treatment with inhibitors targeting fucosylation or sialylation decreases prostate cancer cell growth and downregulates the expression of genes and proteins important in the trajectory of disease progression. We anticipate our findings will lead to the broader use of metabolic inhibitors to explore the role of fucosylated and sialylated glycans in prostate tumor pathology and may pave the way for the development of new therapies for prostate cancer

The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer

Patterns of glycosylation are important in cancer, but the molecular mechanisms that drive changes are often poorly understood. The androgen receptor drives prostate cancer (PCa) development and progression to lethal metastatic castration-resistant disease. Here we used RNA-Seq coupled with bioinformatic analyses of androgen-receptor (AR) binding sites and clinical PCa expression array data to identify ST6GalNAc1 as a direct and rapidly activated target gene of the AR in PCa cells. ST6GalNAc1 encodes a sialytransferase that catalyses formation of the cancer-associated sialyl-Tn antigen (sTn), which we find is also induced by androgen exposure. Androgens induce expression of a novel splice variant of the ST6GalNAc1 protein in PCa cells. This splice variant encodes a shorter protein isoform that is still fully functional as a sialyltransferase and able to induce expression of the sTn-antigen. Surprisingly, given its high expression in tumours, stable expression of ST6GalNAc1 in PCa cells reduced formation of stable tumours in mice, reduced cell adhesion and induced a switch towards a more mesenchymal-like cell phenotype in vitro. ST6GalNAc1 has a dynamic expression pattern in clinical datasets, beingsignificantly up-regulated in primary prostate carcinoma but relatively down-regulated in established metastatic tissue. ST6GalNAc1 is frequently upregulated concurrently with another important glycosylation enzyme GCNT1 previously associated with prostate cancer progression and implicated in Sialyl Lewis X antigen synthesis. Together our data establishes an androgen-dependent mechanism for sTn antigen expression in PCa, and are consistent with a general role for the androgen receptor in driving important coordinate changes to the glycoproteome during PCa progression

Transformation-induced changes in the DNA-nuclear matrix interface, revealed by high-throughput analysis of DNA halos

In higher eukaryotic nuclei, DNA is periodically anchored to an extraction-resistant protein structure, via matrix attachment regions. We describe a refined and accessible method to non-subjectively, rapidly and reproducibly measure both size and stability of the intervening chromatin loops, and use it to demonstrate that malignant transformation compromises the DNA-nuclear matrix interface