Epigenetic regulation of androgen dependent and independent prostate cancer.

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.

Dissecting SOX2 expression and function reveals an association with multiple signaling pathways during embryonic development and in cancer progression.

SRY (Sex Determining Region) box 2 (SOX2) is an essential transcription factor that plays crucial roles in activating genes involved in pre- and post-embryonic development, adult tissue homeostasis, and lineage specifications. SOX2 maintains the self-renewal property of stem cells and is involved in the generation of induced pluripotency stem cells. SOX2 protein contains a particular high-mobility group domain that enables SOX2 to achieve the capacity to participate in a broad variety of functions. The information about the involvement of SOX2 with gene regulatory elements, signaling networks, and microRNA is gradually emerging, and the higher expression of SOX2 is functionally relevant to various cancer types. SOX2 facilitates the oncogenic phenotype via cellular proliferation and enhancement of invasive tumor properties. Evidence are accumulating in favor of three dimensional (higher order) folding of chromatin and epigenetic control of the SOX2 gene by chromatin modifications, which implies that the expression level of SOX2 can be modulated by epigenetic regulatory mechanisms, specifically, via DNA methylation and histone H3 modification. In view of this, and to focus further insights into the roles SOX2 plays in physiological functions, involvement of SOX2 during development, precisely, the advances of our knowledge in pre- and post-embryonic development, and interactions of SOX2 in this scenario with various signaling pathways in tumor development and cancer progression, its potential as a therapeutic target against many cancers are summarized and discussed in this article.

Liquid-liquid phase separation in subcellular assemblages and signaling pathways: Chromatin modifications induced gene regulation for cellular physiology and functions including carcinogenesis.

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.

Molecular mechanisms in regulation of autophagy and apoptosis in view of epigenetic regulation of genes and involvement of liquid-liquid phase separation.

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.

KDM5A noncanonically binds antagonists MLL1/2 to mediate gene regulation and promotes epithelial to mesenchymal transition.

Differential expression of genes involved in certain processes is a collaborative outcome of crosstalk between signalling molecules and epigenetic modifiers. In response to environmental stimulus, interplay between transcription factors and epigenetic modifiers together dictates the regulation of genes. MLLs and KDM5A are functionally antagonistic proteins, as one acts as a writer and the other erases the active chromatin mark, i.e., H3K4me3. KDM5A influences the process of EMT by binding to both epithelial and mesenchymal gene promoters. Through this work, we show that when bound to E-cadherin promoter, KDM5A acts as a classical repressor by demethylating H3K4me3, but on mesenchymal markers, it acts as a transcriptional activator by inhibiting the activity of HDACs and increasing H3K18ac. Further, through our chromatin immunoprecipitation experiments, we observed a co-occupancy of KDM5A with MLLs, we tested whether KDM5A might physically interact with MLLs and WDR5, and here we provide experimental evidence that KDM5A indeed interacts with MLLs and WDR5.

Overexpression of SOX2 Gene by Histone Modifications: SOX2 Enhances Human Prostate and Breast Cancer Progression by Prevention of Apoptosis and Enhancing Cell Proliferation.

INTRODUCTION: SOX2 plays a crucial role in tumor development, cancer stem cell maintenance, and cancer progression. Mechanisms of SOX2 gene regulation in human breast and prostate cancers are not established yet. METHODS: SOX2 expression in prostate and breast cancer tissues and cell lines was determined by qRT-PCR, Western blot, and immunochemistry, followed by the investigation of pro-tumorigenic properties like cell proliferation, migration, and apoptosis by gene knockdown and treatment with epigenetic modulators and ChIP. RESULTS: Prostate and breast cancer tissues showed very high expression of SOX2. All cancer cell lines DU145 and PC3 (prostate) and MCF7 and MDA-MB-231 (breast) exhibited high expression of SOX2. Inhibition of SOX2 drastically decreased cell proliferation and migration. Epigenetic modulators enhanced SOX2 gene expression in both cancer types. DNA methylation pattern in SOX2 promoter could not be appreciably counted for SOX2 overexpression. Activation of SOX2 gene promoter was due to very high deposition of H3K4me3 and H3K9acS10p and drastic decrease of H3K9me3 and H3K27me3. CONCLUSION: Histone modification is crucial for the overexpression of SOX2 during tumor development and cancer progression. These findings show the avenue of co-targeting SOX2 and its active epigenetic modifier enzymes to effectively treat aggressive prostate and breast cancers.

Mechanisms of hedgehog, calcium and retinoic acid signalling pathway inhibitors: Plausible modes of action along the MLL-EZH2-p53 axis in cellular growth control.

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.

Mechanistic aspects of reversible methylation modifications of arginine and lysine of nuclear histones and their roles in human colon cancer.

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.

Epigenetic regulation of pluripotency inducer genes NANOG and SOX2 in human prostate cancer.

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.

Lipid Raft Facilitated Receptor Organization and Signaling: A Functional Rheostat in Embryonic Development, Stem Cell Biology and Cancer.

Molecular views of plasma membrane organization and dynamics are gradually changing over the past fifty years. Dynamics of plasma membrane instigate several signaling nexuses in eukaryotic cells. The striking feature of plasma membrane dynamics is that, it is internally transfigured into various subdomains of clustered macromolecules. Lipid rafts are nanoscale subdomains, enriched with cholesterol and sphingolipids, reside as floating entity mostly on the exoplasmic leaflet of the lipid bilayer. In terms of functionality, lipid rafts are unique among other membrane subdomains. Herein, advances on the roles of lipid rafts in cellular physiology and homeostasis are discussed, precisely, on how rafts dynamically harbor signaling proteins, including GPCRs, catalytic receptors, and ionotropic receptors within it and orchestrate multiple signaling pathways. In the developmental proceedings signaling are designed for patterning of overall organism and they differ from the somatic cell physiology and signaling of fully developed organisms. Some of the developmental signals are characteristic in maintenance of stemness and activated during several types of tumor development and cancer progression. The harmony between extracellular signaling and lineage specific transcriptional programs are extremely important for embryonic development. The roles of plasma membrane lipid rafts mediated signaling in lineage specificity, early embryonic development, stem cell maintenance are emerging. In view of this, we have highlighted and analyzed the roles of lipid rafts in receptor organization, cell signaling, and gene expression during embryonic development; from pre-implantation through the post-implantation phase, in stem cell and cancer biology.

Epigenetic perspectives of COVID-19: Virus infection to disease progression and therapeutic control.

COVID-19 has caused numerous deaths as well as imposed social isolation and upheaval world-wide. Although, the genome and the composition of the virus, the entry process and replication mechanisms are well investigated from by several laboratories across the world, there are many unknown remaining questions. For example, what are the functions of membrane lipids during entry, packaging and exit of virus particles? Also, the metabolic aspects of the infected tissue cells are poorly understood. In the course of virus replication and formation of virus particles within the host cell, the enhanced metabolic activities of the host is directly proportional to viral loads. The epigenetic landscape of the host cells is also altered, particularly the expression/repression of genes associated with cellular metabolism as well as cellular processes that are antagonistic to the virus. Metabolic pathways are enzyme driven processes and the expression profile and mechanism of regulations of the respective genes encoding those enzymes during the course of pathogen invasion might be highly informative on the course of the disease. Recently, the metabolic profile of the patients' sera have been analysed from few patients. In view of this, and to gain further insights into the roles that epigenetic mechanisms might play in this scenario in regulation of metabolic pathways during the progression of COVID-19 are discussed and summarised in this contribution for ensuring best therapy.

PAX9 reactivation by inhibiting DNA methyltransferase triggers antitumor effect in oral squamous cell carcinoma.

Aberrant DNA hypermethylation is associated with oral carcinogenesis. Procaine, a local anesthetic, is a DNA methyltransferase (DNMT) inhibitor that activates anticancer mechanisms. However, its effect on silenced tumor suppressor gene (TSG) activation and its biological role in oral squamous cell carcinoma (OSCC) remain unknown. Here, we report procaine inhibited DNA methylation by suppressing DNMT activity and increased the expression of PAX9, a differentiation gene in OSCC cells. Interestingly, the reactivation of PAX9 by procaine found to inhibit cell growth and trigger apoptosis in OSCC in vitro and in vivo. Likely, the enhanced PAX9 expression after exposure to procaine controls stemness and differentiation through the autophagy-dependent pathway in OSCC cells. PAX9 inhibition abrogated procaine-induced apoptosis, autophagy, and inhibition of stemness. In OSCC cells, procaine improved anticancer drug sensitivity through PAX9, and its deficiency significantly blunted the anticancer drug sensitivity mediated by procaine. Additionally, NRF2 activation by procaine facilitated the antitumor response of PAX9, and pharmacological inhibition of NRF2 by ML385 reduced death and prevented the decrease in the orosphere-forming potential of OSCC cells. Furthermore, procaine promoted antitumor activity in FaDu xenografts in athymic nude mice, and immunohistochemistry data showed that PAX9 expression was significantly enhanced in the procaine group compared to the vehicle control. In conclusion, PAX9 reactivation in response to DNMT inhibition could trigger a potent antitumor mechanism to provide a new therapeutic strategy for OSCC.

Inflammasomes in cancer: Effect of epigenetic and autophagic modulations.

Tumour-promoting inflammation is a critical hallmark in cancer development, and inflammasomes are well-known regulators of inflammatory processes within the tumour microenvironment. Different inflammasome components along with the adaptor, apoptosis-associated speck-like protein containing caspase activation and recruitment domain (ASC), and the effector, caspase-1, have a significant influence on tumorigenesis but in a tissue-specific and stage-dependent manner. The downstream products of inflammasome activation, that is the proinflammatory cytokines such as IL-1ß and IL-18, regulate tissue homeostasis and induce antitumour immune responses, but in contrast, they can also favour cancer growth and proliferation by directing various oncogenic signalling pathways in cancer cells. Moreover, different epigenetic mechanisms, including DNA methylation, histone modification and noncoding RNAs, control inflammasomes and their components by regulating gene expression during cancer progression. Furthermore, autophagy, a master controller of cellular homeostasis, targets inflammasome-induced carcinogenesis by maintaining cellular homeostasis and removing potential cancer risk factors that promote inflammasome activation in support of tumorigenesis. Here, in this review, we summarize the effect of inflammasome activation in cancers and discuss the role of epigenetic and autophagic regulatory mechanisms in controlling inflammasomes. A proper understanding of the interactions among these key processes will be useful for developing novel therapeutic regimens for targeting inflammasomes in cancer.

Metabostemness in cancer: Linking metaboloepigenetics and mitophagy in remodeling cancer stem cells.

Cancer stem cells (CSCs) are rare populations of malignant cells with stem cell-like features of self-renewal, uninterrupted differentiation, tumorigenicity, and resistance to conventional therapeutic agents, and these cells have a decisive role in treatment failure and tumor relapse. The self-renewal potential of CSCs with atypical activation of developmental signaling pathways involves the maintenance of stemness to support cancer progression. The acquisition of stemness in CSCs has been accomplished through genetic and epigenetic rewiring following the metabolic switch. In this context, "metabostemness" denotes the metabolic parameters that essentially govern the epitranscriptional gene reprogramming mechanism to dedifferentiate tumor cells into CSCs. Several metabolites often referred to as oncometabolites can directly remodel chromatin structure and thereby influence the operation of epitranscriptional circuits. This integrated metaboloepigenetic dimension of CSCs favors the differentiated cells to move in dedifferentiated macrostates. Some metabolic events might perform as early drivers of epitranscriptional reprogramming; however, subsequent metabolic hits may govern the retention of stemness properties in the tumor mass. Interestingly, selective removal of mitochondria through autophagy can promote metabolic plasticity and alter metabolic states during differentiation and dedifferentiation. In this connection, novel metabostemness-specific drugs can be generated as potential cancer therapeutics to target the metaboloepigenetic circuitry to eliminate CSCs.

Dietary polyphenols in chemoprevention and synergistic effect in cancer: Clinical evidences and molecular mechanisms of action.

BACKGROUND: Epidemiological studies has revealed that a diet rich in fruits and vegetables could lower the risk of certain cancers. In this setting, natural polyphenols are potent anticancer bioactive compounds to overcome the non-target specificity, undesirable cytotoxicity and high cost of treatment cancer chemotherapy. PURPOSE: The review focuses on diverse classifications of the chemical diversity of dietary polyphenol and their molecular targets, modes of action, as well as preclinical and clinical applications in cancer prevention. RESULTS: The dietary polyphenols exhibit chemo-preventive activity through modulation of apoptosis, autophagy, cell cycle progression, inflammation, invasion and metastasis. Polyphenols possess strong antioxidant activity and control multiple molecular events through activation of tumor suppressor genes and inhibition of oncogenes involved in carcinogenesis. Numerous in vitro and in vivo studies have evidenced that these dietary phytochemicals regulate critical molecular targets and pathways to limit cancer initiation and progression. Moreover, natural polyphenols act synergistically with existing clinically approved drugs. The improved anticancer activity of combinations of polyphenols and anticancer drugs represents a promising perspective for clinical applications against many human cancers. CONCLUSION: The anticancer properties exhibited by dietary polyphenols are mainly attributed to their anti-metastatic, anti-proliferative, anti-angiogenic, anti-inflammatory, cell cycle arrest, apoptotic and autophagic effects. Hence, regular consumption of dietary polyphenols as food or food additives or adjuvants can be a promising tactic to preclude adjournment or cancer therapy.

The clinical significance and correlative signaling pathways of paired box gene 9 in development and carcinogenesis.

Paired box 9 (PAX9) gene belongs to the PAX family, which encodes a family of metazoan transcription factors documented by a conserved DNA binding paired domain 128-amino-acids, critically essential for physiology and development. It is primarily expressed in embryonic tissues, such as the pharyngeal pouch endoderm, somites, neural crest-derived mesenchyme, and distal limb buds. PAX9 plays a vital role in craniofacial development by maintaining the odontogenic potential, mutations, and polymorphisms associated with the risk of tooth agenesis, hypodontia, and crown size in dentition. The loss-of-function of PAX9 in the murine model resulted in a short life span due to the arrest of cleft palate formation and skeletal abnormalities. According to recent studies, the PAX9 gene has a significant role in maintaining squamous cell differentiation, odontoblast differentiation of pluripotent stem cells, deregulation of which is associated with tumor initiation, and malignant transformation. Moreover, PAX9 contributes to promoter hypermethylation and alcohol- induced oro-esophageal squamous cell carcinoma mediated by downregulation of differentiation and apoptosis. Likewise, PAX9 activation is also reported to be associated with drug sensitivity. In summary, this current review aims to understand PAX9 function in the regulation of development, differentiation, and carcinogenesis, along with the underlying signaling pathways for possible cancer therapeutics.

Clusterin as modulator of carcinogenesis: A potential avenue for targeted cancer therapy.

Clusterin (CLU) is an evolutionary conserved molecular chaperone present in different human tissues and fluids and established to be a significant cancer regulator. It controls several cancer-associated cellular events, including cancer cell proliferation, stemness, survival, metastasis, epithelial-mesenchymal transition, therapy resistance, and inhibition of programmed cell death to support cancer growth and recurrence. This multifunctional role of CLU makes it an ideal target for cancer control. More importantly, genetic and antisense-mediated (OGX-011) inhibition of CLU enhances the anticancer potential of different FDA-approved chemotherapeutic drugs at the clinical level, improving patient's survival. In this review, we have discussed the detailed mechanism of CLU-mediated modulation of different cancer-associated signaling pathways. We have also provided updated information on the current preclinical and clinical findings that drive trials in various cancer types for potential targeted cancer therapy.

Secretory clusterin promotes oral cancer cell survival via inhibiting apoptosis by activation of autophagy in AMPK/mTOR/ULK1 dependent pathway.

AIMS: Secretory clusterin (sCLU) plays an important role in tumor development and cancer progression. However, the molecular mechanisms and physiological functions of sCLU in oral cancer is unclear. We examined the impact of sCLU-mediated autophagy in cell survival and apoptosis inhibition in oral cancer. MAIN METHODS: Immunohistochemical analysis was performed to analyze protein expression in patient samples. Autophagy and mitophagy was studied by immunofluorescence microscopy and Western blot. The gain and loss of function was studied by overexpression of plasmid and siRNA approaches respectively. Cellular protection against nutrient starvation and therapeutic stress by sCLU was studied by cell viability, caspase assay and meta-analysis. KEY FINDINGS: The data from oral cancer patients showed that the expression levels of sCLU, ATG14, ULK1, and PARKIN increased in grade-wise manners. Interestingly, sCLU overexpression promoted autophagy through AMPK/Akt/mTOR signaling pathway leading to cell survival and protection from long exposure serum starvation induced-apoptosis. Additionally, sCLU was demonstrated to interact with ULK1 and inhibition of ULK1 activity by SBI206965 was found to abolish sCLU-induced autophagy indicating critical role of ULK1 in induction of autophagy. Furthermore, sCLU was observed to promote expression of mitophagy-associated proteins in serum starvation conditions to protect cells from nutrient deprivation. The meta-analysis elucidated that high CLU expression is associated with therapy resistance in cancer and we demonstrated that sCLU-mediated mitophagy was revealed to inhibit cell death by cisplatin. SIGNIFICANCE: The present investigation has highlighted the probable implications of the clusterin-induced autophagy in cell survival and inhibition of apoptosis in oral cancer.

Emerging histone glutamine modifications mediated gene expression in cell differentiation and the VTA reward pathway.

Gene expression is the key to cellular functions and homeostasis. Histone modifications regulate chromatin dynamics and gene expression. Neuronal cell functions largely depend on fluxes of neurotransmitters for activation of chromatin and gene expression. New studies by Lepack et al. and Farrelly et al. recently demonstrated how tissue transglutaminase 2 (TGM2) mediated histone glutamine modifications, either dopaminylation in the dopaminergic reward pathway or serotonylation in the context of cellular differentiation and signaling regulate gene expression and decipher striking differences from their known functions. This opens new avenues of research in the field of epigenetics in general and neuroepigenetics as special; and to find out the enzymes responsible for the reversible reaction of histone de-dopaminylation and de-serotonylation.

Dissecting miRNA facilitated physiology and function in human breast cancer for therapeutic intervention.

MicroRNAs (miRNAs) are key epigenomic regulators of biological processes in animals and plants. These small non coding RNAs form a complex networks that regulate cellular function and development. MiRNAs prevent translation by either inactivation or inducing degradation of mRNA, a major concern in post-transcriptional gene regulation. Aberrant regulation of gene expression by miRNAs is frequently observed in cancer. Overexpression of various 'oncomiRs' and silencing of tumor suppressor miRNAs are associated with various types of human cancers, although overall downregulation of miRNA expression is reported as a hallmark of cancer. Modulations of the total pool of cellular miRNA by alteration in genetic and epigenetic factors associated with the biogenesis of miRNA machinery. It also depends on the availability of cellular miRNAs from its store in the organelles which affect tumor development and cancer progression. Here, we have dissected the roles and pathways of various miRNAs during normal cellular and molecular functions as well as during breast cancer progression. Recent research works and prevailing views implicate that there are two major types of miRNAs; (i) intracellular miRNAs and (ii) extracellular miRNAs. Concept, that the functions of intracellular miRNAs are driven by cellular organelles in mammalian cells. Extracellular miRNAs function in cell-cell communication in extracellular spaces and distance cells through circulation. A detailed understanding of organelle driven miRNA function and the precise role of extracellular miRNAs, pre- and post-therapeutic implications of miRNAs in this scenario would open several avenues for further understanding of miRNA function and can be better exploited for the treatment of breast cancers.