RESUMEN
Prostate cancer is one of the most common malignancies among men worldwide. Besides genetic alterations, epigenetic modulations including DNA methylation, histone modifications and miRNA mediated alteration of gene expression are the key driving forces for the prostate tumor development and cancer progression. Aberrant expression and/or the activity of the epigenetic modifiers/enzymes, results in aberrant expression of genes involved in DNA repair, cell cycle regulation, cell adhesion, apoptosis, autophagy, tumor suppression and hormone response and thereby disease progression. Altered epigenome is associated with prostate cancer recurrence, progression, aggressiveness and transition from androgen-dependent to androgen-independent phenotype. These epigenetic modifications are reversible and various compounds/drugs targeting the epigenetic enzymes have been developed that are effective in cancer treatment. This chapter focuses on the epigenetic alterations in prostate cancer initiation and progression, listing different epigenetic biomarkers for diagnosis and prognosis of the disease and their potential as therapeutic targets. This chapter also summarizes different epigenetic drugs approved for prostate cancer therapy and the drugs available for clinical trials.
Asunto(s)
Metilación de ADN , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Metilación de ADN/genética , Andrógenos/metabolismo , AnimalesRESUMEN
Liquid-liquid phase separation (LLPS) describes many biochemical processes, including hydrogel formation, in the integrity of macromolecular assemblages and existence of membraneless organelles, including ribosome, nucleolus, nuclear speckles, paraspeckles, promyelocytic leukemia (PML) bodies, Cajal bodies (all exert crucial roles in cellular physiology), and evidence are emerging day by day. Also, phase separation is well documented in generation of plasma membrane subdomains and interplay between membranous and membraneless organelles. Intrinsically disordered regions (IDRs) of biopolymers/proteins are the most critical sticking regions that aggravate the formation of such condensates. Remarkably, phase separated condensates are also involved in epigenetic regulation of gene expression, chromatin remodeling, and heterochromatinization. Epigenetic marks on DNA and histones cooperate with RNA-binding proteins through their IDRs to trigger LLPS for facilitating transcription. How phase separation coalesces mutant oncoproteins, orchestrate tumor suppressor genes expression, and facilitated cancer-associated signaling pathways are unravelling. That autophagosome formation and DYRK3-mediated cancer stem cell modification also depend on phase separation is deciphered in part. In view of this, and to linchpin insight into the subcellular membraneless organelle assembly, gene activation and biological reactions catalyzed by enzymes, and the downstream physiological functions, and how all these events are precisely facilitated by LLPS inducing organelle function, epigenetic modulation of gene expression in this scenario, and how it goes awry in cancer progression are summarized and presented in this article.
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Carcinogénesis , Transducción de Señal , Humanos , Carcinogénesis/genética , Carcinogénesis/metabolismo , Epigénesis Genética , Animales , Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/patología , Cromatina/metabolismo , Cromatina/genética , Orgánulos/metabolismo , Orgánulos/genética , Ensamble y Desensamble de Cromatina , Separación de FasesRESUMEN
Cellular physiology is critically regulated by multiple signaling nexuses, among which cell death mechanisms play crucial roles in controlling the homeostatic landscape at the tissue level within an organism. Apoptosis, also known as programmed cell death, can be induced by external and internal stimuli directing the cells to commit suicide in unfavourable conditions. In contrast, stress conditions like nutrient deprivation, infection and hypoxia trigger autophagy, which is lysosome-mediated processing of damaged cellular organelle for recycling of the degraded products, including amino acids. Apparently, apoptosis and autophagy both are catabolic and tumor-suppressive pathways; apoptosis is essential during development and cancer cell death, while autophagy promotes cell survival under stress. Moreover, autophagy plays dual role during cancer development and progression by facilitating the survival of cancer cells under stressed conditions and inducing death in extreme adversity. Despite having two different molecular mechanisms, both apoptosis and autophagy are interconnected by several crosslinking intermediates. Epigenetic modifications, such as DNA methylation, post-translational modification of histone tails, and miRNA play a pivotal role in regulating genes involved in both autophagy and apoptosis. Both autophagic and apoptotic genes can undergo various epigenetic modifications and promote or inhibit these processes under normal and cancerous conditions. Epigenetic modifiers are uniquely important in controlling the signaling pathways regulating autophagy and apoptosis. Therefore, these epigenetic modifiers of both autophagic and apoptotic genes can act as novel therapeutic targets against cancers. Additionally, liquid-liquid phase separation (LLPS) also modulates the aggregation of misfolded proteins and provokes autophagy in the cytosolic environment. This review deals with the molecular mechanisms of both autophagy and apoptosis including crosstalk between them; emphasizing epigenetic regulation, involvement of LLPS therein, and possible therapeutic approaches against cancers.
Asunto(s)
Epigénesis Genética , Neoplasias , Humanos , Separación de Fases , Apoptosis/genética , Autofagia/genética , Transducción de Señal/fisiología , Neoplasias/genéticaRESUMEN
Mechanical forces may be generated within a cell due to tissue stiffness, cytoskeletal reorganization, and the changes (even subtle) in the cell's physical surroundings. These changes of forces impose a mechanical tension within the intracellular protein network (both cytosolic and nuclear). Mechanical tension could be released by a series of protein-protein interactions often facilitated by membrane lipids, lectins and sugar molecules and thus generate a type of signal to drive cellular processes, including cell differentiation, polarity, growth, adhesion, movement, and survival. Recent experimental data have accentuated the molecular mechanism of this mechanical signal transduction pathway, dubbed mechanotransduction. Mechanosensitive proteins in the cell's plasma membrane discern the physical forces and channel the information to the cell interior. Cells respond to the message by altering their cytoskeletal arrangement and directly transmitting the signal to the nucleus through the connection of the cytoskeleton and nucleoskeleton before the information despatched to the nucleus by biochemical signaling pathways. Nuclear transmission of the force leads to the activation of chromatin modifiers and modulation of the epigenetic landscape, inducing chromatin reorganization and gene expression regulation; by the time chemical messengers (transcription factors) arrive into the nucleus. While significant research has been done on the role of mechanotransduction in tumor development and cancer progression/metastasis, the mechanistic basis of force-activated carcinogenesis is still enigmatic. Here, in this review, we have discussed the various cues and molecular connections to better comprehend the cellular mechanotransduction pathway, and we also explored the detailed role of some of the multiple players (proteins and macromolecular complexes) involved in mechanotransduction. Thus, we have described an avenue: how mechanical stress directs the epigenetic modifiers to modulate the epigenome of the cells and how aberrant stress leads to the cancer phenotype.
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Cromatina , Neoplasias , Humanos , Cromatina/genética , Cromatina/metabolismo , Mecanotransducción Celular/fisiología , Núcleo Celular/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Regulación de la Expresión Génica , Epigénesis GenéticaRESUMEN
Chromatin modifications - including DNA methylation, modification of histones and recruitment of noncoding RNAs - are essential epigenetic events. Multiple sequential modifications converge into a complex epigenetic landscape. For example, promoter DNA methylation is recognized by MeCP2/methyl CpG binding domain proteins which further recruit SETDB1/SUV39 to attain a higher order chromatin structure by propagation of inactive epigenetic marks like H3K9me3. Many studies with new information on different epigenetic modifications and associated factors are available, but clear maps of interconnected pathways are also emerging. This review deals with the salient epigenetic crosstalk mechanisms that cells utilize for different cellular processes and how deregulation or aberrant gene expression leads to disease progression.
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Histonas , Transducción de Señal , Humanos , Progresión de la Enfermedad , Epigénesis Genética , Proteína 2 de Unión a Metil-CpG , Cromatina/genéticaRESUMEN
Developmental proceedings and maintenance of cellular homeostasis are regulated by the precise orchestration of a series of epigenetic events that eventually control gene expression. DNA methylation and post-translational modifications (PTMs) of histones are well-characterized epigenetic events responsible for fine-tuning gene expression. PTMs of histones bear molecular logic of gene expression at chromosomal territory and have become a fascinating field of epigenetics. Nowadays, reversible methylation on histone arginine and lysine is gaining increasing attention as a significant PTM related to reorganizing local nucleosomal structure, chromatin dynamics, and transcriptional regulation. It is now well-accepted and reported that histone marks play crucial roles in colon cancer initiation and progression by encouraging abnormal epigenomic reprogramming. It is becoming increasingly clear that multiple PTM marks at the N-terminal tails of the core histones cross-talk with one another to intricately regulate DNA-templated biological processes such as replication, transcription, recombination, and damage repair in several malignancies, including colon cancer. These functional cross-talks provide an additional layer of message, which spatiotemporally fine-tunes the overall gene expression regulation. Nowadays, it is evident that several PTMs instigate colon cancer development. How colon cancer-specific PTM patterns or codes are generated and how they affect downstream molecular events are uncovered to some extent. Future studies would address more about epigenetic communication, and the relationship between histone modification marks to define cellular functions in depth. This chapter will comprehensively highlight the importance of histone arginine and lysine-based methylation modifications and their functional cross-talk with other histone marks from the perspective of colon cancer development.
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Neoplasias del Colon , Histonas , Humanos , Histonas/metabolismo , Lisina , Arginina/genética , Arginina/metabolismo , Metilación de ADN , Procesamiento Proteico-Postraduccional , Neoplasias del Colon/genéticaRESUMEN
The cells of multicellular organisms are genetically homogeneous but heterogenous in structure and function by virtue of differential gene expression. During embryonic development, differential gene expression by modification of chromatin (DNA and histone complex) regulates the developmental proceedings before and after the germ layers are formed. Post-replicative DNA modification, where the fifth carbon atom of the cytosine gets methylated (hereafter, DNA methylation), does not incorporate mutations within the DNA. In the past few years, a boom has been observed in the field of research related to various epigenetic regulation models, which includes DNA methylation, post-translational modification of histone tails, control of chromatin structure by non-coding RNAs, and remodeling of nucleosome. Epigenetic effects like DNA methylation or histone modification play a cardinal role in development but also be able to arise stochastically, as observed during aging, in tumor development and cancer progression. Over the past few decades, researchers allured toward the involvement of pluripotency inducer genes in cancer progression and apparent for prostate cancer (PCa); also, PCa is the most diagnosed tumor worldwide and comes to the second position in causing mortality in men. The anomalous articulation of pluripotency-inducing transcription factor; SRY-related HMG box-containing transcription factor-2 (SOX2), Octamer-binding transcription factor 4 (OCT4) or POU domain, class 5, transcription factor 1 (POU5F1), and NANOG have been reported in different cancers which includes breast cancer, tongue cancer, and lung cancer, etc. Although there is a variety in gene expression signatures demonstrated by cancer cells, the epigenetic mode of regulation at the pluripotency-associated genes in PCa has been recently explored. This chapter focuses on the epigenetic control of NANOG and SOX2 genes in human PCa and the precise role thereof executed by the two transcription factors.
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Proteínas de Homeodominio , Neoplasias de la Próstata , Masculino , Humanos , Proteínas de Homeodominio/metabolismo , Histonas/metabolismo , Epigénesis Genética , Proteína Homeótica Nanog/genética , Proteína Homeótica Nanog/metabolismo , Metilación de ADN , Cromatina , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismoRESUMEN
BACKGROUND: Intensive Care Unit (ICU) nurses have a vital role in the implementation of end of life (EOL) care. There is limited data on the attitude of ICU nurses toward EOL and palliation. AIM: This study aimed to investigate knowledge, attitude, and beliefs of intensive care nurses in eastern India toward EOL. MATERIALS AND METHODS: A self-administered questionnaire was distributed to delegates in two regional critical care nurses' training programs. RESULTS: Of 178 questionnaires distributed, 138 completed, with a response rate of 75.5*. About half (48.5*) had more than 1 year ICU experience. A majority (81.9*) agreed that nurses should be involved in and initiate (62.3*) EOL discussions. Terms "EOL care or palliative care in ICU" were new for 19.6*; 21* and 55.8* disagreed with allowing peaceful death in terminal patients and unrestricted family visits, respectively. Work experience was associated with wanting unrestricted family visitation, discontinuing monitoring and investigations at EOL, equating withholding and withdrawal of treatment, and being a part of EOL team discussions (P = 0.005, 0.01, 0.01, and 0.001), respectively. Religiousness was associated with a greater desire to initiate EOL discussions (P = 0.001). CONCLUSION: Greater emphasis on palliative care in critical care curriculum may improve awareness among critical care nurses.