Deferiprone: new environmental perspectives. Insights into its sequestering ability vs. different metal cations.

Deferiprone, generally, is considered an important chelating agent for Fe3+ overload. From a literature data analysis, a lack of information on the interaction of this molecule toward a series of metal cations emerged, inducing to fill out the topic. The complexing ability of deferiprone toward Ca2+, Mg2+, Cd2+ and Pb2+ was studied by potentiometry and 1H NMR spectroscopy, in KCl aqueous solutions at different ionic strength values (0.1 ≤ I/mol dm-3 ≤ 1.0) and T = 298.15 K. The same speciation model featured by the ML, ML2, ML3 and ML(OH) (M = metal and L = deferiprone or DFP) species was obtained for Cd2+ and Pb2+; the formation constants calculated at infinite dilution are: logTß = 7.23±0.02, 12.47±0.03, 16.70±0.04, and -2.53±0.04, respectively for Cd2+ and 9.91±0.01, 15.99±0.02, 19.93±0.05 and 0.99±0.02 for Pb2+. Only two species, namely ML and ML2, were determined for Ca2+ and Mg2+, whose formation constants at infinite dilution are respectively: 3.72±0.01 and 6.50±0.02, for the first one, 5.31±0.01 and 9.58±0.01, for the second. The ligand sequestering ability and affinity toward M2+ were evaluated by determining the pL0.5 and pM parameters at different pHs and ionic strengths. The results suggest that deferiprone has the best complexing and sequestering ability toward Pb2+, followed by Cd2+, Mg2+ and Ca2+, respectively. 1H NMR studies confirmed the DFP affinity for Cd2+ and Pb2+, and in combination with DFT calculations showed that metal cations are bound to the hydroxo-oxo moiety of the pyridinone ring. The data reported in this study provide information on the possible employment of a small molecule like deferiprone, as a chelating and sequestering agent for Pb2+ accumulation or overload from environmental and biological matrices.

Marine Natural Products with Activities against Prostate Cancer: Recent Discoveries.

Prostate cancer is the most common cancer in men, with over 52,000 new cases diagnosed every year. Diagnostics and early treatment are potentially hindered by variations in screening protocols, still largely reliant on serum levels of acid phosphatase and prostate-specific antigen, with tumour diagnosis and grading relying on histopathological examination. Current treatment interventions vary in terms of efficacy, cost and severity of side effects, and relapse can be aggressive and resistant to the current standard of care. For these reasons, the scientific community is looking for new chemotherapeutic agents. This review reports compounds and extracts derived from marine organisms as a potential source of new drugs against prostate cancer. Whilst there are several marine-derived compounds against other cancers, such as multiple myeloma, leukemia, breast and lung cancer, already available in the market, the presently collated findings show how the marine environment can be considered to hold potential as a new drug source for prostate cancer, as well. This review presents information on compounds presently in clinical trials, as well as new compounds/extracts that may enter trials in the future. We summarise information regarding mechanisms of action and active concentrations.

The Long Non-Coding RNA H19 Drives the Proliferation of Diffuse Intrinsic Pontine Glioma with H3K27 Mutation.

Diffuse intrinsic pontine glioma (DIPG) is an incurable paediatric malignancy. Identifying the molecular drivers of DIPG progression is of the utmost importance. Long non-coding RNAs (lncRNAs) represent a large family of disease- and tissue-specific transcripts, whose functions have not yet been elucidated in DIPG. Herein, we studied the oncogenic role of the development-associated H19 lncRNA in DIPG. Bioinformatic analyses of clinical datasets were used to measure the expression of H19 lncRNA in paediatric high-grade gliomas (pedHGGs). The expression and sub-cellular location of H19 lncRNA were validated in DIPG cell lines. Locked nucleic acid antisense oligonucleotides were designed to test the function of H19 in DIPG cells. We found that H19 expression was higher in DIPG vs. normal brain tissue and other pedHGGs. H19 knockdown resulted in decreased cell proliferation and survival in DIPG cells. Mechanistically, H19 buffers let-7 microRNAs, resulting in the up-regulation of oncogenic let-7 target (e.g., SULF2 and OSMR). H19 is the first functionally characterized lncRNA in DIPG and a promising therapeutic candidate for treating this incurable cancer.

The Effect of Metal Cations on the Aqueous Behavior of Dopamine. Thermodynamic Investigation of the Binary and Ternary Interactions with Cd2+, Cu2+ and UO22+ in NaCl at Different Ionic Strengths and Temperatures.

The interactions of dopamine [2-(3,4-Dihydroxyphenyl)ethylamine, (Dop-)] with cadmium(II), copper(II) and uranyl(VI) were studied in NaCl(aq) at different ionic strengths (0 ≤ I/mol dm-3 ≤ 1.0) and temperatures (288.15 ≤ T/K ≤ 318.15). From the elaboration of the experimental data, it was found that the speciation models are featured by species of different stoichiometry and stability. In particular for cadmium, the formation of only MLH, ML and ML2 (M = Cd2+; L = dopamine) species was obtained. For uranyl(VI) (UO22+), the speciation scheme is influenced by the use of UO2(acetate)2 salt as a chemical; in this case, the formation of ML2, MLOH and the ternary MLAc (Ac = acetate) species in a wide pH range was observed. The most complex speciation model was obtained for the interaction of Cu2+ with dopamine; in this case we observed the formation of the following species: ML2, M2L, M2L2, M2L2(OH)2, M2LOH and ML2OH. These speciation models were determined at each ionic strength and temperature investigated. As a further contribution to this kind of investigation, the ternary interactions of dopamine with UO22+/Cd2+ and UO22+/Cu2+ were investigated at I = 0.15 mol dm-3 and T = 298.15K. These systems have different speciation models, with the MM'L and M2M'L2OH [M = UO22+; M' = Cd2+ or Cu2+, L = dopamine] common species; the species of the mixed Cd2+ containing system have a higher stability with respect the Cu2+ containing one. The dependence on the ionic strength of complex formation constants was modelled by using both an extended Debye-Hückel equation that included the Van't Hoff term for the calculation of the formation enthalpy change values and the Specific Ion Interaction Theory (SIT). The results highlighted that, in general, the entropy is the driving force of the process. The quantification of the effective sequestering ability of dopamine towards the studied cations was evaluated by using a Boltzmann-type equation and the calculation of pL0.5 parameter. The sequestering ability was quantified at different ionic strengths, temperatures and pHs, and this resulted, in general, that the pL0.5 trend was always: UO22+ > Cu2+ > Cd2+.

Bifunctional 3-Hydroxy-4-Pyridinones as Potential Selective Iron(III) Chelators: Solution Studies and Comparison with Other Metals of Biological and Environmental Relevance.

The binding ability of five bifunctional 3-hydroxy-4-pyridinones towards Cu2+ and Fe3+ was studied by means of potentiometric and UV-Vis spectrophotometric measurements carried out at I = 0.15 mol L-1 in NaCl(aq),T = 298.15 K and 310.15 K. The data treatments allowed us to determine speciation schemes featured by metal-ligand species with different stoichiometry and stability, owing to the various functional groups present in the 3-hydroxy-4-pyridinones structures, which could potentially participate in the metal complexation, and in the Cu2+ and Fe3+ behaviour in aqueous solution. Furthermore, the sequestering ability and metal chelating affinity of the ligands were investigated by the determination of pL0.5 and pM parameters at different pH conditions. Finally, a comparison between the Cu2+ and Fe3+/3-hydroxy-4-pyridinones data herein presented with those already reported in the literature on the interaction of Zn2+ and Al3+ with the same ligands showed that, from the thermodynamic point of view, the 3-hydroxy-4-pyridinones are particularly selective towards Fe3+ and could therefore be considered promising iron-chelating agents, also avoiding the possibility of competition, and eventually the depletion, of essential metal cations of biological and environmental relevance, such as Cu2+ and Zn2+.

The Open University's first one-day symposium on treatment-emergent neuroendocrine prostate cancer.

The Open University's first one-day symposium on treatment-emergent neuroendocrine prostate cancer attracted world-leading figures, early career researchers and industry colleagues. The symposium proved insightful into the 'real-world' impact and current problems faced in the diagnosis and treatment of neuroendocrine prostate cancer. It was important for this meeting to take place as the incidence of neuroendocrine prostate cancer is increasing due to the widespread use of next-generation androgen deprivation drugs. The symposium discussions proposed new molecularly driven deadlines to accelerate research and improved the treatment of this deadly and poorly recognized malignancy.

Special Issue "Chemical Speciation of Organic and Inorganic Components of Environmental and Biological Interest in Natural Fluids: Behaviour, Interaction and Sequestration".

Several different definitions were in the past proposed to describe the term chemical speciation, and some of them were accepted from the scientific community [...].

Understanding the Solution Behavior of Epinephrine in the Presence of Toxic Cations: A Thermodynamic Investigation in Different Experimental Conditions.

The interactions of epinephrine ((R)-(-)-3,4-dihydroxy-α-(methylaminomethyl)benzyl alcohol; Eph-) with different toxic cations (methylmercury(II): CH3Hg+; dimethyltin(IV): (CH3)2Sn2+; dioxouranium(VI): UO22+) were studied in NaClaq at different ionic strengths and at T = 298.15 K (T = 310.15 K for (CH3)2Sn2+). The enthalpy changes for the protonation of epinephrine and its complex formation with UO22+ were also determined using isoperibolic titration calorimetry: HHL = -39 ± 1 kJ mol-1, HH2L = -67 ± 1 kJ mol-1 (overall reaction), HML = -26 ± 4 kJ mol-1, and HM2L2(OH)2 = 39 ± 2 kJ mol-1. The results were that UO22+ complexation by Eph- was an entropy-driven process. The dependence on the ionic strength of protonation and the complex formation constants was modeled using the extended Debye-Hückel, specific ion interaction theory (SIT), and Pitzer approaches. The sequestering ability of adrenaline toward the investigated cations was evaluated using the calculation of pL0.5 parameters. The sequestering ability trend resulted in the following: UO22+ >> (CH3)2Sn2+ > CH3Hg+. For example, at I = 0.15 mol dm-3 and pH = 7.4 (pH = 9.5 for CH3Hg+), pL0.5 = 7.68, 5.64, and 2.40 for UO22+, (CH3)2Sn2+, and CH3Hg+, respectively. Here, the pH is with respect to ionic strength in terms of sequestration.

T-type calcium channels drive the proliferation of androgen-receptor negative prostate cancer cells.

BACKGROUND: Androgen deprivation therapy (ADT) is the treatment of choice for metastatic prostate cancer (PCa). After an initial response to ADT, PCa cells can generate castration resistant (CRPC) or neuroendocrine (NEPC) malignancies, which are incurable. T-type calcium channels (TTCCs) are emerging as promising therapeutic targets for several cancers, but their role in PCa progression has never been investigated. METHODS: To examine the role of TTCCs in PCa, we analyzed their expression level, copy number variants (CNV) and prognostic significance using clinical datasets (Oncomine and cBioPortal). We then evaluated TTCC expression in a panel of PCa cell lines and measured the effect of their inhibition on cell proliferation and survival using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and caspase assays. RESULTS: TTCCs were upregulated in PCas harboring androgen receptor (AR) mutations; CNV rate was positively associated with PCa progression. Higher expression of one TTCC isoform (CACNA1G) predicted poorer postoperative prognosis in early stage PCa samples. Pharmacological or small interfering RNA (siRNA)-based inhibition of TTCCs caused a decrease in PC-3 cell survival and proliferation. CONCLUSIONS: Our results show that TTCCs are overexpressed in advanced forms of PCa and correlate with a poorer prognosis. TTCC inhibition reduces cell proliferation and survival, suggesting that there may be possible value in the therapeutic targeting of TTCCs in advanced PCa.

Speciation Studies of Bifunctional 3-Hydroxy-4-Pyridinone Ligands in the Presence of Zn2+ at Different Ionic Strengths and Temperatures.

The acid-base properties of two bifunctional 3-hydroxy-4-pyridinone ligands and their chelating capacity towards Zn2+, an essential bio-metal cation, were investigated in NaCl aqueous solutions by potentiometric, UV-Vis spectrophotometric, and 1H NMR spectroscopic titrations, carried out at 0.15 ≤ I/mol -1 ≤ 1.00 and 288.15 ≤ T/K ≤ 310.15. A study at I = 0.15 mol L-1 and T = 298.15 K was also performed for other three Zn2+/Lz- systems, with ligands belonging to the same family of compounds. The processing of experimental data allowed the determination of protonation and stability constants, which showed accordance with the data obtained from the different analytical techniques used, and with those reported in the literature for the same class of compounds. ESI-MS spectrometric measurements provided support for the formation of the different Zn2+/ligand species, while computational molecular simulations allowed information to be gained on the metal-ligand coordination. The dependence on ionic strength and the temperature of equilibrium constants were investigated by means of the extended Debye-Hückel model, the classical specific ion interaction theory, and the van't Hoff equations, respectively.

The IONA® Test: Development of an Automated Cell-Free DNA-Based Screening Test for Fetal Trisomies 13, 18, and 21 That Employs the Ion Proton Semiconductor Sequencing Platform.

OBJECTIVE: To develop a screening test for fetal trisomy 13, 18, and 21 using cell-free DNA from maternal blood with an automated workflow using the Ion Proton sequencing platform. METHODS: An automated next-generation sequencing workflow was developed using the Ion Proton sequencing platform and software developed for straightforward bioinformatic analysis. An algorithm was developed using 239 samples to determine the likelihood of trisomy, using DNA fragment counts and a fetal fraction validity check; the results were compared with those from invasive diagnostic procedures. A further 111 samples were used to assess the tests' sensitivity (detection rate) and specificity (1 minus false-positive rate). RESULTS: The 110 of a possible 111 valid samples used to verify the IONA® test gave 100% sensitivity and specificity, compared with invasive diagnostic procedures; one failed the fetal fraction validity check giving a sample failure rate of 0.29% across all 350 analysed samples. CONCLUSION: The data indicate that the IONA test provides a robust, accurate automated workflow suitable for use on maternal blood samples to screen for trisomies 13, 18, and 21. The test has the potential to reduce the number of unnecessary invasive procedures performed and facilitate testing by screening laboratories.

The potential role of PHF6 as an oncogene: a genotranscriptomic/proteomic meta-analysis.

Epigenetic complexes control various pathways within the cells. Their abnormalities can be involved in the initiation and the progression of different types of cancer. Nucleosome remodeling and deacetylase (NuRD) is an epigenetic complex that comprises several subunits such as PHF6. Although PHF6 is reported as a tumor suppressor in some of the hematopoietic malignancies, its function is still challenging in other cancers. Our study aimed at investigating the role of PHF6 in different types of cancer. We conducted a meta-analysis of PHF6 in human cancers at genomic, transcriptomic, and proteomic levels. For this purpose, we acquired the data from several databases, and tried to statistically integrate and analyze the data in order to find the potential role of PHF6 in different tumors. The results demonstrated that although PHF6 has been previously known as a tumor suppressor gene, it was remarkably overexpressed in many cancer types such as breast and colorectal cancers. Notably, PHF6 was under-expressed in a few types of cancer, including esophageal tumors. Moreover, the results indicated that although the mutation rate of PHF6 is relatively low, it is mutated in some tumor types.  In addition, our data for 40 epigenetic genes showed that missense and nonsense mutations were associated with overexpression and under-expression, respectively. Our results suggest that PHF6 may function as an oncogenic factor in several types of cancer. We also hypothesize that PHF6 may also play its role in a tissue-specific manner. Our findings suggest further investigations regarding the exact role of PHF6 in tumor types.

Topoisomerase 1 Promoter Variants and Benefit from Irinotecan in Metastatic Colorectal Cancer Patients.

OBJECTIVE: Topoisomerase 1 (topo-1) is an important target for the treatment of metastatic colorectal cancer (CRC). The aim of the present study was to evaluate the correlation between topo-1 single-nucleotide polymorphisms (SNPs) and clinical outcome in metastatic CRC (mCRC) patients. METHODS: With the use of specific software (PROMO 3.0), we performed an in silico analysis of topo-1 promoter SNPs; the rs6072249 and rs34282819 SNPs were included in the study. DNA was extracted from 105 mCRC patients treated with FOLFIRI ± bevacizumab in the first line. SNP genotyping was performed by real-time PCR. Genotypes were correlated with clinical parameters (objective response rate, progression-free survival, and overall survival). RESULTS: No single genotype was significantly associated with clinical variables. The G allelic variant of rs6072249 topo-1 SNP is responsible for GC factor and X-box-binding protein transcription factor binding. The same allelic variant showed a nonsignificant trend toward a shorter progression-free survival (GG, 7.5 months; other genotypes, 9.3 months; HR 1.823, 95% CI 0.8904-3.734; p = 0.1). CONCLUSION: Further analyses are needed to confirm that the topo-1 SNP rs6072249 and transcription factor interaction could be a part of tools to predict clinical outcome in mCRC patients treated with irinotecan-based regimens.

The long non-coding RNA PCGEM1 is regulated by androgen receptor activity in vivo.

BACKGROUND: Long non-coding RNAs (lncRNAs) can orchestrate oncogenic or tumor-suppressive functions in cancer biology. Accordingly, PCGEM1 and PRNCR1 were implicated in progression of prostate cancer (PCa) as transcriptional co-regulators of the androgen receptor (AR). However, these findings were recently refuted asserting that neither gene physically binds to the AR. Despite evidence for differing AR transcriptional programs in vivo and in vitro, studies investigating AR-regulation of these genes hitherto have only been conducted in vitro. Here, we further examine the relevance of PCGEM1 and PRNCR1 in PCa, and their relationship with AR signaling, using patient-derived xenograft models. FINDINGS: RNA sequencing of two distinct androgen-dependent models shows PCGEM1 to be considerably expressed, while PRNCR1 showed scant basal expression. PCGEM1 was sharply down-regulated following castration and up-regulated upon AR activation in vivo. However, we found no parallel evidence following AR stimulation in vitro. A PCGEM1-associated gene expression signature (PES) was significantly repressed in response to androgen ablation therapy and in hormone-refractory versus hormone-naïve PCa patients. Furthermore, we found PCGEM1 was uniformly distributed in PCa cell nucleus and cytoplasm which remained unaltered upon AR transcriptional activation. PCGEM1 was up-regulated in primary PCa but not in metastasized PCa. Accordingly, the PES was significantly down-regulated in advanced and higher grade PCa patients from multiple independent studies. CONCLUSION: Our results demonstrate PCGEM1 as an in vivo androgen-regulated transcript with potential nuclear and/or cytoplasmic function(s). Importantly, the clinical expression profile of PCGEM1 implicates it in the early stages of PCa warranting further research in this direction.

The non-coding transcriptome as a dynamic regulator of cancer metastasis.

Since the discovery of microRNAs, non-coding RNAs (NC-RNAs) have increasingly attracted the attention of cancer investigators. Two classes of NC-RNAs are emerging as putative metastasis-related genes: long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs). LncRNAs orchestrate metastatic progression through several mechanisms, including the interaction with epigenetic effectors, splicing control and generation of microRNA-like molecules. In contrast, snoRNAs have been long considered "housekeeping" genes with no relevant function in cancer. However, recent evidence challenges this assumption, indicating that some snoRNAs are deregulated in cancer cells and may play a specific role in metastasis. Interestingly, snoRNAs and lncRNAs share several mechanisms of action, and might synergize with protein-coding genes to generate a specific cellular phenotype. This evidence suggests that the current paradigm of metastatic progression is incomplete. We propose that NC-RNAs are organized in complex interactive networks which orchestrate cellular phenotypic plasticity. Since plasticity is critical for cancer cell metastasis, we suggest that a molecular interactome composed by both NC-RNAs and proteins orchestrates cancer metastasis. Interestingly, expression of lncRNAs and snoRNAs can be detected in biological fluids, making them potentially useful biomarkers. NC-RNA expression profiles in human neoplasms have been associated with patients' prognosis. SnoRNA and lncRNA silencing in pre-clinical models leads to cancer cell death and/or metastasis prevention, suggesting they can be investigated as novel therapeutic targets. Based on the literature to date, we critically discuss how the NC-RNA interactome can be explored and manipulated to generate more effective diagnostic, prognostic, and therapeutic strategies for metastatic neoplasms.

Molecular and pathological characterization of the EZH2 rs3757441 single nucleotide polymorphism in colorectal cancer.

BACKGROUND: The enhancer of zeste-homolog 2 (EZH2) is involved in cancer development through gene silencing by trimethylation of lysine 27 of histone 3 (H3K27me3). The C/C genotype for the EZH2 rs3757441 single-nucleotide polymorphism (SNP) is linked with poor prognosis in metastatic colorectal cancer (CRC), but molecular and pathological characterization of this SNP is lacking. METHODS: 119 primary CRCs were analyzed. SNP was evaluated by real-time PCR from colonic healthy tissue, while EZH2 and H3K27me3 expression were studied by immunohistochemistry. We primarily looked for correlation between EZH2 rs3757441 genotypes and EZH2/H3K27me3 expression. Potential associations between EZH2/H3K27me3 expression and clinico-pathological features or KRAS exon 2 and BRAF exon 15 mutations were secondary endpoints. Statistical analysis was performed by chi-square test, T-test or ANOVA. RESULTS: The C/C genotype was significantly associated with higher EZH2 (100 vs. 44 %; P = 0.019) and H3K27me3 (100 vs. 38 %; P = 0.009) staining intensity compared with C/T and T/T. EZH2 3+ staining significantly correlated with stronger H3K27me3 expression (P = 0.039). KRAS and BRAF mutations were not associated with EZH2 or H3K27me3 expression. CONCLUSION: EZH2 rs3757441 C/C genotype is associated with stronger EZH2 and H3K27me3 immunoreactivity in primary CRC: this SNP may serve as a promising biomarker for EZH2-targeting agents and may add independent information to KRAS and BRAF testing.

Comprehensive analysis of differentially expressed miRNAs in hepatocellular carcinoma: Prognostic, predictive significance and pathway insights.

Robust prognostic and predictive factors for hepatocellular carcinoma, a leading cause of cancer-related deaths worldwide, have not yet been identified. Previous studies have identified potential HCC determinants such as genetic mutations, epigenetic alterations, and pathway dysregulation. However, the clinical significance of these molecular alterations remains elusive. MicroRNAs are major regulators of protein expression. MiRNA functions are frequently altered in cancer. In this study, we aimed to explore the prognostic value of differentially expressed miRNAs in HCC, to elucidate their associated pathways and their impact on treatment response. To this aim, bioinformatics techniques and clinical dataset analyses were employed to identify differentially expressed miRNAs in HCC compared to normal hepatic tissue. We validated known associations and identified a novel miRNA signature with potential prognostic significance. Our comprehensive analysis identified new miRNA-targeted pathways and showed that some of these protein coding genes predict HCC patients' response to the tyrosine kinase inhibitor sorafenib.

Biopolymeric Nanocomposites for CO2 Capture.

Carbon dioxide (CO2) impacts the greenhouse effect significantly and results in global warming, prompting urgent attention to climate change concerns. In response, CO2 capture has emerged as a crucial process to capture carbon produced in industrial and power processes before its release into the atmosphere. The main aim of CO2 capture is to mitigate the emissions of greenhouse gas and reduce the anthropogenic impact on climate change. Biopolymer nanocomposites offer a promising avenue for CO2 capture due to their renewable nature. These composites consist of biopolymers derived from biological sources and nanofillers like nanoparticles and nanotubes, enhancing the properties of the composite. Various biopolymers like chitosan, cellulose, carrageenan, and others, possessing unique functional groups, can interact with CO2 molecules. Nanofillers are incorporated to improve mechanical, thermal, and sorption properties, with materials such as graphene, carbon nanotubes, and metallic nanoparticles enhancing surface area and porosity. The CO2 capture mechanism within biopolymer nanocomposites involves physical absorption, chemisorption, and physisorption, driven by functional groups like amino and hydroxyl groups in the biopolymer matrix. The integration of nanofillers further boosts CO2 adsorption capacity by increasing surface area and porosity. Numerous advanced materials, including biopolymeric derivatives like cellulose, alginate, and chitosan, are developed for CO2 capture technology, offering accessibility and cost-effectiveness. This semi-systematic literature review focuses on recent studies involving biopolymer-based materials for CO2 capture, providing an overview of composite materials enriched with nanomaterials, specifically based on cellulose, alginate, chitosan, and carrageenan; the choice of these biopolymers is dictated by the lack of a literature perspective focused on a currently relevant topic such as these biorenewable resources in the framework of carbon capture. The production and efficacy of biopolymer-based adsorbents and membranes are examined, shedding light on potential trends in global CO2 capture technology enhancement.

Deciphering the Transcription Factor Landscape in Neuroendocrine Prostate Cancer Progression: A Novel Approach to Understand NE Transdifferentiation.

Background and Objective: Prostate cancer (PCa) is a leading cause of cancer mortality in men, with neuroendocrine prostate cancer (NEPC) representing a particularly resistant subtype. The role of transcription factors (TFs) in the progression from prostatic adenocarcinoma (PRAD) to NEPC is poorly understood. This study aims to identify and analyze lineage-specific TF profiles in PRAD and NEPC and illustrate their dynamic shifts during NE transdifferentiation. Methods: A novel algorithmic approach was developed to evaluate the weighted expression of TFs within patient samples, enabling a nuanced understanding of TF landscapes in PCa progression and TF dynamic shifts during NE transdifferentiation. Results: unveiled TF profiles for PRAD and NEPC, identifying 126 shared TFs, 46 adenocarcinoma-TFs, and 56 NEPC-TFs. Enrichment analysis across multiple clinical cohorts confirmed the lineage specificity and clinical relevance of these lineage-TFs signatures. Functional analysis revealed that lineage-TFs are implicated in pathways critical to cell development, differentiation, and lineage determination. Novel lineage-TF candidates were identified, offering potential targets for therapeutic intervention. Furthermore, our longitudinal study on NE transdifferentiation highlighted dynamic TF expression shifts and delineated a three-phase hypothesis for the process comprised of de-differentiation, dormancy, and re-differentiation. and proposing novel insights into the mechanisms of PCa progression. Conclusion: The lineage-specific TF profiles in PRAD and NEPC reveal a dynamic shift in the TF landscape during PCa progression, highlighting three distinct phases of NE transdifferentiation.

EZH2 inhibition: targeting the crossroad of tumor invasion and angiogenesis.

Tumor angiogenesis and metastatic spreading are two highly interconnected phenomena, which contribute to cancer-associated deaths. Thus, the identification of novel strategies to target angiogenesis and metastatic spreading is crucial. Polycomb genes are a set of epigenetic effectors, structured in multimeric repressive complexes. EZH2 is the catalytic subunit of Polycomb repressive complex 2 (PRC2), which methylates histone H3 lysine 27, thereby silencing several tumor-suppressor genes. EZH2 is essential for cancer stem cell self-renewal. Interestingly, cancer stem cells are thought to be the seeds of metastatic spreading and are able to differentiate into tumor-associated endothelial cells. Pre-clinical studies showed that EZH2 is able to silence several anti-metastatic genes (e.g., E-cadherin and tissue inhibitors of metalloproteinases), thereby favoring cell invasion and anchorage-independent growth. In addition, EZH2 seems to play a crucial role in the regulation of tumor angiogenesis. High EZH2 expression predicts poor prognosis, high grade, and high stage in several cancer types. Recently, a small molecule inhibitor of PRC2 (DZNeP) demonstrated promising anti-tumor activity, both in vitro and in vivo. Interestingly, DZNeP was able to inhibit cancer cell invasion and tumor angiogenesis in prostate and brain cancers, respectively. At tumor-inhibiting doses, DZNeP is not harmful for non-transformed cells. In the present manuscript, we review current evidence supporting a role of EZH2 in metastatic spreading and tumor angiogenesis. Using Oncomine datasets, we show that DZNeP targets are specifically silenced in some metastatic cancers, and some of them may inhibit angiogenesis. Based on this evidence, we propose the development of EZH2 inhibitors as anti-angiogenic and anti-metastatic therapy.