RESUMO
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.
Assuntos
Metilação de DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Metilação de DNA/genética , Androgênios/metabolismo , AnimaisRESUMO
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.
Assuntos
Carcinogênese , Transdução de Sinais , Humanos , Carcinogênese/genética , Carcinogênese/metabolismo , Epigênese Genética , Animais , Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/patologia , Cromatina/metabolismo , Cromatina/genética , Organelas/metabolismo , Organelas/genética , Montagem e Desmontagem da Cromatina , Separação de FasesRESUMO
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.
Assuntos
Epigênese Genética , Neoplasias , Humanos , Separação de Fases , Apoptose/genética , Autofagia/genética , Transdução de Sinais/fisiologia , Neoplasias/genéticaRESUMO
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.
Assuntos
Cromatina , Neoplasias , Humanos , Cromatina/genética , Cromatina/metabolismo , Mecanotransdução Celular/fisiologia , Núcleo Celular/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Regulação da Expressão Gênica , Epigênese GenéticaRESUMO
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.
Assuntos
Histonas , Transdução de Sinais , Humanos , Progressão da Doença , Epigênese Genética , Proteína 2 de Ligação a Metil-CpG , Cromatina/genéticaRESUMO
Understanding the molecular mechanism(s) of small compounds in cellular growth control are essential for using those against the disease(s). Oral cancers exhibit a very high mortality rate due to higher metastatic potential. Aberrant EGFR, RAR, HH signalling, enhanced [Ca2+] and oxidative stress are some of the important characteristics of oral cancer. So, we target these for our study. Herein, we tested the effect of fendiline hydrochloride (FH) as an LTCC Ca2+-channel inhibitor, erismodegib (a SMO inhibitor of HH-signalling) and all-trans retinoic acid (RA) inducer of RAR signalling that causes cellular differentiation. OCT4 activating compound (OAC1) counters differentiation and induces stemness properties. Cytosine ß-D arabinofuranoside (Cyto-BDA), a DNA replication inhibitor was used to reduce high proliferative capacity. Treatment of FaDu cells with OAC1, Cyto-BDA and FH increase G0/G1 population by 3%, 20% and 7% respectively, and lead to reduction of cyclin D1, CDK4/6 levels. Erismodegib arrests the cells in S-phase with reduced cyclin-E1&A1 levels, whereas RA-treatment causes G2/M phase arrest with reduced cyclin-B1. There was a decrease in the expression of EGFR and mesenchymal markers, Snail/Slug/Vim/Zeb/Twist, and increased E-cadherin expression in all the drug treatments, indicating a reduction in proliferative signal and EMT. Enhanced MLL2 (Mll4) and reduced EZH2 expression associated overexpression of p53 and p21 were traced out. We conclude that these drugs impact expression of epigenetic modifiers by modulating signalling pathways and the epigenetic modifiers then controls the expression of cell cycle control genes, including p53 and p21.