Epi-miRNAs: Regulators of the Histone Modification Machinery in Human Cancer

Cancer is a leading cause of death and disability worldwide. Epigenetic deregulation is one of the most critical mechanisms in carcinogenesis and can be classified into effects on DNA methylation and histone modification. MicroRNAs are small noncoding RNAs involved in fine-tuning their target genes after transcription. Various microRNAs control the expression of histone modifiers and are involved in a variety of cancers. Therefore, overexpression or downregulation of microRNAs can alter cell fate and cause malignancies. In this review, we discuss the role of microRNAs in regulating the histone modification machinery in various cancers, with a focus on the histone-modifying enzymes such as acetylases, deacetylases, methyltransferases, demethylases, kinases, phosphatases, desumoylases, ubiquitinases, and deubiquitinases. Understanding of microRNA-related aberrations underlying histone modifiers in pathogenesis of different cancers can help identify novel therapeutic targets or early detection approaches that allow better management of patients or monitoring of treatment response.

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 5: Epigenetic Regulation of PD-L1

Epigenetic alterations (including DNA methylation or miRNAs) influence oncogene/oncosuppressor gene expression without changing the DNA sequence. Prostate cancer (PC) displays a complex genetic and epigenetic regulation of cell-growth pathways and tumor progression. We performed a systematic literature review (following PRISMA guidelines) focused on the epigenetic regulation of PD-L1 expression in PC. In PC cell lines, CpG island methylation of the CD274 promoter negatively regulated PD-L1 expression. Histone modifiers also influence the PD-L1 transcription rate: the deletion or silencing of the histone modifiers MLL3/MML1 can positively regulate PD-L1 expression. Epigenetic drugs (EDs) may be promising in reprogramming tumor cells, reversing epigenetic modifications, and cancer immune evasion. EDs promoting a chromatin-inactive transcriptional state (such as bromodomain or p300/CBP inhibitors) downregulated PD-L1, while EDs favoring a chromatin-active state (i.e., histone deacetylase inhibitors) increased PD-L1 expression. miRNAs can regulate PD-L1 at a post-transcriptional level. miR-195/miR-16 were negatively associated with PD-L1 expression and positively correlated to longer biochemical recurrence-free survival; they also enhanced the radiotherapy efficacy in PC cell lines. miR-197 and miR-200a-c positively correlated to PD-L1 mRNA levels and inversely correlated to the methylation of PD-L1 promoter in a large series. miR-570, miR-34a and miR-513 may also be involved in epigenetic regulation.

The PPARα and PPARγ Epigenetic Landscape in Cancer and Immune and Metabolic Disorders

Peroxisome proliferator-activated receptors (PPARs) are ligand-modulated nuclear receptors that play pivotal roles in nutrient sensing, metabolism, and lipid-related processes. Correct control of their target genes requires tight regulation of the expression of different PPAR isoforms in each tissue, and the dysregulation of PPAR-dependent transcriptional programs is linked to disorders, such as metabolic and immune diseases or cancer. Several PPAR regulators and PPAR-regulated factors are epigenetic effectors, including non-coding RNAs, epigenetic enzymes, histone modifiers, and DNA methyltransferases. In this review, we examine advances in PPARα and PPARγ-related epigenetic regulation in metabolic disorders, including obesity and diabetes, immune disorders, such as sclerosis and lupus, and a variety of cancers, providing new insights into the possible therapeutic exploitation of PPAR epigenetic modulation.

Viral Manipulation of the Host Epigenome as a Driver of Virus-Induced Oncogenesis

Tumorigenesis due to viral infection accounts for a high fraction of the total global cancer burden (15–20%) of all human cancers. A comprehensive understanding of the mechanisms by which viral infection leads to tumor development is extremely important. One of the main mechanisms by which viruses induce host cell proliferation programs is through controlling the host’s epigenetic machinery. In this review, we dissect the epigenetic pathways through which oncogenic viruses can integrate their genome into host cell chromosomes and lead to tumor progression. In addition, we highlight the potential use of drugs based on histone modifiers in reducing the global impact of cancer development due to viral infection.

An Updated Review of the Cross-talk between MicroRNAs and Epigenetic Factors in Cancers

Background: Growing evidence indicates that miRs have critical activities in adjusting cellular processes, e.g., cell death, proliferation, and cell-cycle. Introduction: This study aimed to provide a concise review of the recent findings regarding tumoral miRs and the cross-talk between miRs and epigenetic factors. Results: Like the protein-coding genes, the expression levels of miRs are mediated by various transcriptional networks. Indeed, the expression of miRs could be epigenetically modulated by DNA methylation factors and histone modifiers. Furthermore, miRs can suppress critical factors, which mediate epigenetic modifications. Besides, miRs have been implicated in cancer development, metastasis, and chemo-resistance. The aberrant expression of miRs and dysregulated modulatory circuits between miRs and epigenetic factors participate in tumor progression. Conclusion: Identifying tumoral miRs can provide ample opportunity to overcome chemo-resistance and bring a forefront treatment for affected patients.

The MLR COMPASS-like complex is required to regulate triglyceride depletion and stress response in the Drosophila fat body

MLR COMPASS-like complexes are highly conserved histone modifiers and enhancer regulators recruited by multiple transcription factors during differentiation and development, including lineage-determining factors, nuclear receptors, and developmental signaling pathway effectors. While the essential functions of MLR complexes during differentiation-associated transcriptional reprogramming has been well-explored, roles that these complexes play during reprogramming events in terminally differentiated cells remain understudied. We determined that the Drosophila MLR complex is required in fat body adipocytes for proper regulation of the triglyceride depletion rate during non-feeding periods, including metamorphosis and adult starvation. Transcriptome analysis revealed that the complex plays a critical role in controlling stress-related reprogramming in these cells, suggesting that the metabolic phenotypes are indirect effects of dysregulated stress transcription. Furthermore, our evidence suggests that the complex interacts with Foxo and Relish (Nf-κb) pathways and is required for proper expression of their targets. This investigation further elucidates the necessary functions of MLR complexes in regulating transcriptional reprogramming in terminally differentiated cells as well as suggests novel binding partners. Apparent roles for these complexes in the proper regulation of stress-induced transcription implies new mechanisms involved in cancer and other human diseases associated with MLR subunit mutation.

Chromatin Modifiers in Transcriptional Regulation: New Findings and Prospects

Histone-modifying and remodeling complexes are considered the main coregulators that affect transcription by changing the chromatin structure. Coordinated action by these complexes is essential for the transcriptional activation of any eukaryotic gene. In this review, we discuss current trends in the study of histone modifiers and chromatin remodelers, including the functional impact of transcriptional proteins/complexes i.e., pioneers; remodeling and modification of non-histone proteins by transcriptional complexes; the supplementary functions of the non-catalytic subunits of remodelers, and the participation of histone modifiers in the pause of RNA polymerase II. The review also includes a scheme illustrating the mechanisms of recruitment of the main classes of remodelers and chromatin modifiers to various sites in the genome and their functional activities.

The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma

Multiple myeloma is a malignancy of terminally differentiated plasma cells, characterized by an extreme genetic heterogeneity that poses great challenges for its successful treatment. Due to antibody overproduction, MM cells depend on the precise regulation of the protein degradation systems. Despite the success of PIs in MM treatment, resistance and adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. To this end, the use of rational combinatorial treatments might allow lowering the dose of inhibitors and therefore, minimize their side-effects. Even though the suppression of different cellular pathways in combination with proteasome inhibitors have shown remarkable anti-myeloma activities in preclinical models, many of these promising combinations often failed in clinical trials. Substantial progress has been made by the simultaneous targeting of proteasome and different aspects of MM-associated immune dysfunctions. Moreover, targeting deranged metabolic hubs could represent a new avenue to identify effective therapeutic combinations with PIs. Finally, epigenetic drugs targeting either DNA methylation, histone modifiers/readers, or chromatin remodelers are showing pleiotropic anti-myeloma effects alone and in combination with PIs. We envisage that the positive outcome of patients will probably depend on the availability of more effective drug combinations and treatment of early MM stages. Therefore, the identification of sensitive targets and aberrant signaling pathways is instrumental for the development of new personalized therapies for MM patients.