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Protein function alteration and protein mislocalization are cancer hallmarks that drive oncogenesis. N6-methyladenosine (m6A) deposition mediated by METTL3, METTL16, and METTL5 together with the contribution of additional subunits of the m6A system, has shown a dramatic impact on cancer development. However, the cellular localization of m6A proteins inside tumor cells has been little studied so far. Interestingly, recent evidence indicates that m6A methyltransferases are not always confined to the nucleus, suggesting that epitranscriptomic factors may also have multiple oncogenic roles beyond m6A that still represent an unexplored field. To date novel epigenetic drugs targeting m6A modifiers, such as METTL3 inhibitors, are entering into clinical trials, therefore, the study of the potential onco-properties of m6A effectors beyond m6A is required. Here we will provide an overview of methylation-independent functions of the m6A players in cancer, describing the molecular mechanisms involved and the future implications for therapeutics.
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BACKGROUND: Breast cancer manifests as a heterogeneous pathology marked by complex metabolic reprogramming essential to satisfy its energy demands. Oncogenic signals boost the metabolism, modifying fatty acid synthesis and glucose use from the onset to progression and therapy resistant-forms. However, the exact contribution of metabolic dependencies during tumor evolution remains unclear. METHODS: In this study, we elucidate the connection between FASN and LDHA, pivotal metabolic genes, and their correlation with tumor grade and therapy response using datasets from public repositories. Subsequently, we evaluated the metabolic and proliferative functions upon FASN and LDHA inhibition in breast cancer models. Lastly, we integrated metabolomic and lipidomic analysis to define the contributions of metabolites, lipids, and precursors to the metabolic phenotypes. RESULTS: Collectively, our findings indicate metabolic shifts during breast cancer progression, unvealling two distinct functional energy phenotypes associated with aggressiveness and therapy response. Specifically, FASN exhibits reduced expression in advance-grade tumors and therapy-resistant forms, whereas LDHA demonstrates higher expression. Additionally, the biological and metabolic impact of blocking the enzymatic activity of FASN and LDHA was correlated with resistant conditions. CONCLUSIONS: These observations emphasize the intrinsic metabolic heterogeneity within breast cancer, thereby highlighting the relevance of metabolic interventions in the field of precision medicine.
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Neoplasias da Mama , Ácido Graxo Sintase Tipo I , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/enzimologia , Feminino , Ácido Graxo Sintase Tipo I/metabolismo , Ácido Graxo Sintase Tipo I/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Lipidômica , Metabolômica , L-Lactato DesidrogenaseRESUMO
Ulcerative colitis (UC), an inflammatory bowel disease (IBD), may increase the risk of colorectal cancer (CRC) by activating chronic proinflammatory pathways. The goal of this study was to find serum prediction biomarkers in UC to CRC development by combining low-density miRNA microarray and biocomputational approaches. The UC and CRC miRNA expression profiles were compared by low-density miRNA microarray, finding five upregulated miRNAs specific to UC progression to CRC (hsa-let-7d-5p, hsa-miR-16-5p, hsa-miR-145-5p, hsa-miR-223-5p, and hsa-miR-331-3p). The circRNA/miRNA/mRNA competitive endogenous RNA (ceRNA) network analysis showed that the candidate miRNAs were connected to well-known colitis-associated CRC ACVR2A, SOCS1, IGF2BP1, FAM126A, and CCDC85C mRNAs, and circ-SHPRH circRNA. SST and SCARA5 genes regulated by hsa-let-7d-5p, hsa-miR-145-5p, and hsa-miR-331-3p were linked to a poor survival prognosis in a CRC patient dataset from The Cancer Genome Atlas (TCGA). Lastly, our mRNA and miRNA candidates were validated by comparing their expression to differentially expressed mRNAs and miRNAs from colitis-associated CRC tissue databases. A high level of hsa-miR-331-3p and a parallel reduction in SOCS1 mRNA were found in tissue and serum. We propose hsa-miR-331-3p and possibly hsa-let-7d-5p as novel serum biomarkers for predicting UC progression to CRC. More clinical sample analysis is required for further validation.
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Biomarcadores Tumorais , Colite Ulcerativa , Neoplasias Colorretais , Perfilação da Expressão Gênica , MicroRNAs , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biomarcadores Tumorais/análise , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Biologia Computacional/métodos , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , MicroRNAs/análise , MicroRNAs/metabolismoRESUMO
Chromatin has an extremely flexible structure that allows the fine regulation of gene expression. To orchestrate this process, small chemical modifications are dynamically added or removed on DNA, RNA and histone substrates. Epigenetic modifications govern a plethora of key cellular functions, whose dysregulation contributes to oncogenesis. The interrelationship between (irreversible) genetic mutations and (reversible) epigenetic alterations and how this crosstalk regulates gene expression has long been a major area of interest. Marks modulating the RNA code (epitranscriptome), such as the well-studied N6 -methyladenosine (m6 A), are known to influence stability, metabolism and life cycle of many mRNAs, including cancer-associated transcripts. Together, epigenetic and epitranscriptomic pathways therefore control the entire cellular expression profile and, eventually, cell fate. Recently, previously undescribed crosstalk between these two pathways has started to be unrevealed. For example, m6 A and its effectors cooperate with histone modifications to localize chromatin-modifying complexes to their target regions. Epigenetic marks governing the expression of m6 A factors can also be found at specific genetic loci. m6 A itself can mark noncoding RNAs (including lncRNAs, circRNAs and miRNAs), influencing their structure, maturation and function. These interactions affect both cell physiology and pathology. Clear evidence that dysregulation of this network plays a role in cancer has emerged, suggesting a new layer of complexity in the landscape of gene expression. Here, we summarize current knowledge on the interplay between m6 A epitranscriptome and epigenome, focusing on cancer processes. We also discuss strategies to target m6 A machinery for future therapeutic intervention.
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MicroRNAs , Neoplasias , Humanos , Epigenoma , Epigênese Genética , Neoplasias/genética , Neoplasias/metabolismo , Cromatina/genéticaRESUMO
Glioblastoma, the most common and heterogeneous tumor affecting brain parenchyma, is dismally characterized by a very poor prognosis. Thus, the search of new, more effective treatments is a vital need. Here, we will review the druggable epigenetic features of glioblastomas that are, indeed, currently explored in preclinical studies and in clinical trials for the development of more effective, personalized treatments. In detail, we will review the studies that have led to the identification of epigenetic signatures, IDH mutations, MGMT gene methylation, histone modification alterations, H3K27 mutations and epitranscriptome landscapes of glioblastomas, in each case discussing the corresponding targeted therapies and their potential efficacy. Finally, we will emphasize how recent technological improvements permit to routinely investigate many glioblastoma epigenetic biomarkers in clinical practice, further enforcing the hope that personalized drugs, targeting specific epigenetic features, could be in future a therapeutic option for selected patients.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/diagnóstico , Glioblastoma/genética , Glioblastoma/terapia , Prognóstico , Proteínas Supressoras de Tumor/genética , Metilação de DNA , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Metilases de Modificação do DNA/genética , Mutação , Epigênese Genética , Enzimas Reparadoras do DNA/genética , Biomarcadores Tumorais/genéticaRESUMO
BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous and aggressive blood cancer that results from diverse genetic aberrations in the hematopoietic stem or progenitor cells (HSPCs) leading to the expansion of blasts in the hematopoietic system. The heterogeneity and evolution of cancer blasts can render therapeutic interventions ineffective in a yet poorly understood patient-specific manner. In this study, we investigated the clonal heterogeneity of diagnosis (Dx) and relapse (Re) pairs at genetic and transcriptional levels, and unveiled the underlying pathways and genes contributing to recurrence. METHODS: Whole-exome sequencing was used to detect somatic mutations and large copy number variations (CNVs). Single cell RNA-seq was performed to investigate the clonal heterogeneity between Dx-Re pairs and amongst patients. RESULTS: scRNA-seq analysis revealed extensive expression differences between patients and Dx-Re pairs, even for those with the same -presumed- initiating events. Transcriptional differences between and within patients are associated with clonal composition and evolution, with the most striking differences in patients that gained large-scale copy number variations at relapse. These differences appear to have significant molecular implications, exemplified by a DNMT3A/FLT3-ITD patient where the leukemia switched from an AP-1 regulated clone at Dx to a mTOR signaling driven clone at Re. The two distinct AML1-ETO pairs share genes related to hematopoietic stem cell maintenance and cell migration suggesting that the Re leukemic stem cell-like (LSC-like) cells evolved from the Dx cells. CONCLUSIONS: In summary, the single cell RNA data underpinned the tumor heterogeneity not only amongst patient blasts with similar initiating mutations but also between each Dx-Re pair. Our results suggest alternatively and currently unappreciated and unexplored mechanisms leading to therapeutic resistance and AML recurrence.
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Variações do Número de Cópias de DNA , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Mutação , Recidiva , Análise de Célula Única , Transcriptoma , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
BACKGROUND: The dynamic epigenome and proteins specialized in the interpretation of epigenetic marks critically contribute to leukemic pathogenesis but also offer alternative therapeutic avenues. Targeting newly discovered chromatin readers involved in leukemogenesis may thus provide new anticancer strategies. Accumulating evidence suggests that the PRC1 complex member CBX2 is overexpressed in solid tumors and promotes cancer cell survival. However, its role in leukemia is still unclear. METHODS: We exploited reverse genetic approaches to investigate the role of CBX2 in human leukemic cell lines and ex vivo samples. We also analyzed phenotypic effects following CBX2 silencing using cellular and molecular assays and related functional mechanisms by ATAC-seq and RNA-seq. We then performed bioinformatic analysis of ChIP-seq data to explore the influence of histone modifications in CBX2-mediated open chromatin sites. Lastly, we used molecular assays to determine the contribution of CBX2-regulated pathways to leukemic phenotype. RESULTS: We found CBX2 overexpressed in leukemia both in vitro and ex vivo samples compared to CD34+ cells. Decreased CBX2 RNA levels prompted a robust reduction in cell proliferation and induction of apoptosis. Similarly, sensitivity to CBX2 silencing was observed in primary acute myeloid leukemia samples. CBX2 suppression increased genome-wide chromatin accessibility followed by alteration of leukemic cell transcriptional programs, resulting in enrichment of cell death pathways and downregulation of survival genes. Intriguingly, CBX2 silencing induced epigenetic reprogramming at p38 MAPK-associated regulatory sites with consequent deregulation of gene expression. CONCLUSIONS: Our results identify CBX2 as a crucial player in leukemia progression and highlight a potential druggable CBX2-p38 MAPK network in AML.
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Cromatina , Leucemia Mieloide Aguda , Complexo Repressor Polycomb 1 , Cromatina/genética , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
We have recently developed a new synthetic methodology that provided both N-aryl-5-hydroxytriazoles and N-pyridine-4-alkyl triazoles. A selection of these products was carried through virtual screening towards targets that are contemporary and validated for drug discovery and development. This study determined a number of potential structure target dyads of which N-pyridinium-4-carboxylic-5-alkyl triazole displayed the highest score specificity towards KAT2A. Binding affinity tests of abovementioned triazole and related analogs towards KAT2A confirmed the predictions of the in-silico assay. Finally, we have run in vitro inhibition assays of selected triazoles towards KAT2A; the ensemble of binding and inhibition assays delivered pyridyl-triazoles carboxylates as the prototype of a new class of inhibitors of KAT2A.
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Acetiltransferases , Triazóis , Ácidos Carboxílicos/química , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologiaRESUMO
Alteration of the chromatin orchestra seems to play a critical role in cancer. In recent years, in-depth studies of epigenetic machinery and its deregulation have led to the development and use of a wide range of modulatory molecules directed not only at chromatin enzymes (histone acetyltransferases, histone deacetylases, histone methyltransferases, histone demethylases and DNA methyltransferases) but also toward the emerging class of chromatin-associated proteins, so-called "histone readers." Chromatin modifiers are attractive therapeutic targets for the development of new cancer therapies. Many are currently approved by the US Food and Drug Administration and used to treat different malignancies. Specifically, inhibitors of DNA methyltransferases, such as azacitidine and decitabine, have been approved for the treatment of myelodysplastic syndrome, while inhibitors of histone deacetylases, including vorinostat and romidepsin, have been approved for cutaneous T-cell lymphoma. The bromodomain and extra-terminal inhibitors JQ1, IBET762 and IBET151 have performed extremely well in preclinical settings, suggesting that they may be promising molecules for the treatment of some type of tumors. This review focuses on epidrugs and their possible application, with particular emphasis on their mechanism of action as well as their present status in clinical and preclinical trials.
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Antineoplásicos/uso terapêutico , Drogas em Investigação/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Modelos Biológicos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Pesquisa Biomédica/tendências , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Desenho de Fármacos , Descoberta de Drogas/tendências , Drogas em Investigação/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismoRESUMO
Background: Hormone receptor-positive tumors are unlikely to exhibit a complete pathological tumor response. The association of CDK 4/6 inhibitor plus hormone therapy has changed this perspective. Case presentation: In this study, we retrospectively reviewed the charts of patients with a diagnosis of luminal A/B advanced/metastatic tumors treated with a CDK 4/6 inhibitor-based therapy. In this part of the study, we present clinical and ultrasound evaluation. Eight female patients were considered eligible for the study aims. Three complete and five partial responses were reported, including a clinical tumor response of 50% or more in five out of nine assessed lesions (55%). All patients showed a response on ultrasound. The mean lesion size measured by ultrasound was 27.1 ± 15.02 mm (range, 6-47 mm) at the baseline; 16.08 ± 14.6 mm (range, 0-40 mm) after 4 months (T1); and 11.7 ± 12.9 mm (range, 0-30 mm) at the 6 months follow-up (T2). Two patients underwent surgery. The radiological complete response found confirmation in a pathological complete response, while the partial response matched a moderate residual disease. Conclusion: The evaluation of breast cancer by ultrasound is basically informative of response and may be an easy and practical tool to monitor advanced tumors, especially in advanced/unfit patients who are reluctant to invasive exams.
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Aging is a pathophysiological process that causes a gradual and permanent reduction in all biological system functions. The phenomenon is caused by the accumulation of endogenous and exogenous damage as a result of several stressors, resulting in significantly increased risks of various age-related diseases such as neurodegenerative diseases, cardiovascular diseases, metabolic diseases, musculoskeletal diseases, and immune system diseases. In addition, aging appears to be connected with mis-regulation of programmed cell death (PCD), which is required for regular cell turnover in many tissues sustained by cell division. According to the recent nomenclature, PCDs are physiological forms of regulated cell death (RCD) useful for normal tissue development and turnover. To some extent, some cell types are connected with a decrease in RCD throughout aging, whereas others are related with an increase in RCD. Perhaps the widespread decline in RCD markers with age is due to a slowdown of the normal rate of homeostatic cell turnover in various adult tissues. As a result, proper RCD regulation requires a careful balance of many pro-RCD and anti-RCD components, which may render cell death signaling pathways more sensitive to maladaptive signals during aging. Current research, on the other hand, tries to further dive into the pathophysiology of aging in order to develop therapies that improve health and longevity. In this scenario, RCD handling might be a helpful strategy for human health since it could reduce the occurrence and development of age-related disorders, promoting healthy aging and lifespan. In this review we propose a general overview of the most recent RCD mechanisms and their connection with the pathophysiology of aging in order to promote targeted therapeutic strategies.
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Doenças Neurodegenerativas , Morte Celular Regulada , Humanos , Envelhecimento/fisiologia , Apoptose/fisiologia , LongevidadeRESUMO
Hematological malignancies are among the top five most frequent forms of cancer in developed countries worldwide. Although the new therapeutic approaches have improved the quality and the life expectancy of patients, the high rate of recurrence and drug resistance are the main issues for counteracting blood disorders. Chemotherapy-resistant leukemic clones activate molecular processes for biological survival, preventing the activation of regulated cell death pathways, leading to cancer progression. In the past decade, leukemia research has predominantly centered around modulating the well-established processes of apoptosis (type I cell death) and autophagy (type II cell death). However, the development of therapy resistance and the adaptive nature of leukemic clones have rendered targeting these cell death pathways ineffective. The identification of novel cell death mechanisms, as categorized by the Nomenclature Committee on Cell Death (NCCD), has provided researchers with new tools to overcome survival mechanisms and activate alternative molecular pathways. This review aims to synthesize information on these recently discovered RCD mechanisms in the major types of leukemia, providing researchers with a comprehensive overview of cell death and its modulation.
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MicroRNA (miRNA) expression profiling is an important tool to identify miRNA regulation in physiological or pathological states. This technique has a large number of molecular diagnostic applications, including cancer, cardiovascular and autoimmune diseases, and forensics. To date, a multitude of high-throughput genomic approaches have been developed. Here, we focus on miRNA expression profiling by microarray using SurePrint technology, providing a description of both the workflow and methods for expression profiling by Agilent One-Color Microarray.
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Doenças Autoimunes , MicroRNAs , Humanos , Análise em Microsséries , Genômica , MicroRNAs/genética , TecnologiaRESUMO
AIM: miRNA-21 is a crucial regulator of developing cardiac diseases, but its role is still controversial, and therefore it is necessary to clarify, at cardiac level, its involvement in high glucose induced-acute and chronic cardiac damage. METHODS: Human ventricular cardiac myoblasts AC16, treated and not with miRNA-21 inhibitor, were exposed to high glucose for 2 and 7 days, and the expression of damage markers were investigated. Further, cardiac energetic metabolism was evaluated by measuring both the expression of glucose transporters and lipids regulators. RESULTS: Short-term high glucose treatment induced a significant increase in miRNA-21 expression (p < 0.05) that was associated with an increase in hydrogen ion flux and energy potential dissipation without any change in energy production or increase in genes expression involved in cellular damage. miRNA-21 reduction observed (p < 0.05) at 7 days of high glucose treatment, induced the activation of damage pathways and compromised mitochondrial function (p < 0.05). CONCLUSION: In human cardiomyocytes, the abundance of miRNA-21 takes part in first defense mechanism against cardiac insult and its cardioprotective effect depends on time of exposure to injury. Moreover, miRNA-21 regulates mitochondrial respiration and the ability of cells to select the most appropriate substrate for ATP production in given environment.
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MicroRNAs , Miócitos Cardíacos , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Apoptose , Linhagem Celular , Glucose/metabolismo , Glucose/farmacologia , Humanos , Lipídeos , MicroRNAs/genética , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , PrótonsRESUMO
Metabolism plays a fundamental role in both human physiology and pathology, including pancreatic ductal adenocarcinoma (PDAC) and other tumors. Anabolic and catabolic processes do not only have energetic implications but are tightly associated with other cellular activities, such as DNA duplication, redox reactions, and cell homeostasis. PDAC displays a marked metabolic phenotype and the observed reduction in tumor growth induced by calorie restriction with in vivo models supports the crucial role of metabolism in this cancer type. The aggressiveness of PDAC might, therefore, be reduced by interventions on bioenergetic circuits. In this review, we describe the main metabolic mechanisms involved in PDAC growth and the biological features that may favor its onset and progression within an immunometabolic context. We also discuss the need to bridge the gap between basic research and clinical practice in order to offer alternative therapeutic approaches for PDAC patients in the more immediate future.
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Glioblastomas are the most frequent and malignant brain tumor hallmarked by an invariably poor prognosis. They have been classically differentiated into primary isocitrate dehydrogenase 1 or 2 (IDH1 -2) wild-type (wt) glioblastoma (GBM) and secondary IDH mutant GBM, with IDH wt GBMs being commonly associated with older age and poor prognosis. Recently, genetic analyses have been integrated with epigenetic investigations, strongly implementing typing and subtyping of brain tumors, including GBMs, and leading to the new WHO 2021 classification. GBM genomic and epigenomic profile influences evolution, resistance, and therapeutic responses. However, differently from other tumors, there is a wide gap between the refined GBM profiling and the limited therapeutic opportunities. In addition, the different oncogenes and tumor suppressor genes involved in glial cell transformation, the heterogeneous nature of cancer, and the restricted access of drugs due to the blood-brain barrier have limited clinical advancements. This review will summarize the more relevant genetic alterations found in GBMs and highlight their potential role as potential therapeutic targets.
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The latest studies identified the histone deacetylase (HDAC) class of enzymes as strategic components of the complex molecular machinery underlying inflammation in cystic fibrosis (CF). Compelling new support has been provided for HDAC6 isoform as a key player in the generation of the dysregulated proinflammatory phenotype in CF, as well as in the immune response to the persistent bacterial infection accompanying CF patients. We herein provide in vivo proof-of-concept (PoC) of the efficacy of selective HDAC6 inhibition in contrasting the pro-inflammatory phenotype in a mouse model of chronic P. aeruginosa respiratory infection. Upon careful selection and in-house re-profiling (in vitro and cell-based assessment of acetylated tubulin level through Western blot analysis) of three potent and selective HDAC6 inhibitors as putative candidates for the PoC, we engaged the best performing compound 2 for pre-clinical studies. Compound 2 demonstrated no toxicity and robust anti-inflammatory profile in a mouse model of chronic P. aeruginosa respiratory infection upon repeated aerosol administration. A significant reduction of leukocyte recruitment in the airways, in particular neutrophils, was observed in compound 2-treated mice in comparison with the vehicle; moreover, quantitative immunoassays confirmed a significant reduction of chemokines and cytokines in lung homogenate. This effect was also associated with a modest reduced bacterial load after compound 2-treatment in mice compared to the vehicle. Our study is of particular significance since it demonstrates for the first time the utility of selective drug-like HDAC6 inhibitors in a relevant in vivo model of chronic P. aeruginosa infection, thus supporting their potential application for reverting CF phenotype.
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Fibrose Cística , Infecções por Pseudomonas , Camundongos , Animais , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/tratamento farmacológico , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Desacetilase 6 de Histona , Pseudomonas aeruginosa , Aerossóis e Gotículas Respiratórios , Inflamação , Modelos Animais de DoençasRESUMO
OBJECTIVE: Aberrant activity of androgen receptor (AR) is the primary cause underlying development and progression of prostate cancer (PCa) and castration-resistant PCa (CRPC). Androgen signaling regulates gene transcription and lipid metabolism, facilitating tumor growth and therapy resistance in early and advanced PCa. Although direct AR signaling inhibitors exist, AR expression and function can also be epigenetically regulated. Specifically, lysine (K)-specific demethylases (KDMs), which are often overexpressed in PCa and CRPC phenotypes, regulate the AR transcriptional program. METHODS: We investigated LSD1/UTX inhibition, two KDMs, in PCa and CRPC using a multi-omics approach. We first performed a mitochondrial stress test to evaluate respiratory capacity after treatment with MC3324, a dual KDM-inhibitor, and then carried out lipidomic, proteomic, and metabolic analyses. We also investigated mechanical cellular properties with acoustic force spectroscopy. RESULTS: MC3324 induced a global increase in H3K4me2 and H3K27me3 accompanied by significant growth arrest and apoptosis in androgen-responsive and -unresponsive PCa systems. LSD1/UTX inhibition downregulated AR at both transcriptional and non-transcriptional level, showing cancer selectivity, indicating its potential use in resistance to androgen deprivation therapy. Since MC3324 impaired metabolic activity, by modifying the protein and lipid content in PCa and CRPC cell lines. Epigenetic inhibition of LSD1/UTX disrupted mitochondrial ATP production and mediated lipid plasticity, which affected the phosphocholine class, an important structural element for the cell membrane in PCa and CRPC associated with changes in physical and mechanical properties of cancer cells. CONCLUSIONS: Our data suggest a network in which epigenetics, hormone signaling, metabolite availability, lipid content, and mechano-metabolic process are closely related. This network may be able to identify additional hotspots for pharmacological intervention and underscores the key role of KDM-mediated epigenetic modulation in PCa and CRPC.
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Histona Desmetilases , Neoplasias de Próstata Resistentes à Castração , Antagonistas de Androgênios/uso terapêutico , Androgênios/metabolismo , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Lipídeos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , ProteômicaRESUMO
Breast cancer (BC) is the second leading cause of cancer death in women, although recent scientific and technological achievements have led to significant improvements in progression-free disease and overall survival of patients. Genetic mutations and epigenetic modifications play a critical role in deregulating gene expression, leading to uncontrolled cell proliferation and cancer progression. Aberrant histone modifications are one of the most frequent epigenetic mechanisms occurring in cancer. In particular, methylation and demethylation of specific lysine residues alter gene accessibility via histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs). The KDM family includes more than 30 members, grouped into six subfamilies and two classes based on their sequency homology and catalytic mechanisms, respectively. Specifically, the KDM4 gene family comprises six members, KDM4A-F, which are associated with oncogene activation, tumor suppressor silencing, alteration of hormone receptor downstream signaling, and chromosomal instability. Blocking the activity of KDM4 enzymes renders them "druggable" targets with therapeutic effects. Several KDM4 inhibitors have already been identified as anticancer drugs in vitro in BC cells. However, no KDM4 inhibitors have as yet entered clinical trials due to a number of issues, including structural similarities between KDM4 members and conservation of the active domain, which makes the discovery of selective inhibitors challenging. Here, we summarize our current knowledge of the molecular functions of KDM4 members in BC, describe currently available KDM4 inhibitors, and discuss their potential use in BC therapy.
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Autophagy is an essential intracellular catabolic mechanism involved in the degradation and recycling of damaged organelles regulating cellular homeostasis and energy metabolism. Its activation enhances cellular tolerance to various stresses and is known to be involved in drug resistance. In cancer, autophagy has a dual role in either promoting or blocking tumorigenesis, and recent studies indicate that epigenetic regulation is involved in its mechanism of action in this context. Specifically, the ubiquitin-binding histone deacetylase (HDAC) enzyme HDAC6 is known to be an important player in modulating autophagy. Epigenetic modulators, such as HDAC inhibitors, mediate this process in different ways and are already undergoing clinical trials. In this review, we describe current knowledge on the role of epigenetic modifications, particularly HDAC-mediated modifications, in controlling autophagy in cancer. We focus on the controversy surrounding their ability to promote or block tumor progression and explore the impact of HDAC6 inhibitors on autophagy modulation in cancer. In light of the fact that targeted drug therapy for cancer patients is attracting ever increasing interest within the research community and in society at large, we discuss the possibility of using HDAC6 inhibitors as adjuvants and/or in combination with conventional treatments to overcome autophagy-related mechanisms of resistance.