The Role of HDAC6 in Glioblastoma Multiforme: A New Avenue to Therapeutic Interventions?

Despite the great advances in basic research results, glioblastoma multiforme (GBM) still remains an incurable tumour. To date, a GBM diagnosis is a death sentence within 15-18 months, due to the high recurrence rate and resistance to conventional radio- and chemotherapy approaches. The effort the scientific community is lavishing on the never-ending battle against GBM is reflected by the huge number of clinical trials launched, about 2003 on 10 September 2024. However, we are still far from both an in-depth comprehension of the biological and molecular processes leading to GBM onset and progression and, importantly, a cure. GBM is provided with high intratumoral heterogeneity, immunosuppressive capacity, and infiltrative ability due to neoangiogenesis. These features impact both tumour aggressiveness and therapeutic vulnerability, which is further limited by the presence in the tumour core of niches of glioblastoma stem cells (GSCs) that are responsible for the relapse of this brain neoplasm. Epigenetic alterations may both drive and develop along GBM progression and also rely on changes in the expression of the genes encoding histone-modifying enzymes, including histone deacetylases (HDACs). Among them, HDAC6-a cytoplasmic HDAC-has recently gained attention because of its role in modulating several biological aspects of GBM, including DNA repair ability, massive growth, radio- and chemoresistance, and de-differentiation through primary cilia disruption. In this review article, the available information related to HDAC6 function in GBM will be presented, with the aim of proposing its inhibition as a valuable therapeutic route for this deadly brain tumour

SARS-CoV-2, Endothelial Dysfunction, and the Renin-Angiotensin System (RAS): A Potentially Dangerous Triad for the Development of Pre-Eclampsia

SARS-CoV-2 represents the greatest epidemiological, clinical, and social challenge the human being has had to face in this century. SARS-CoV-2 is not merely a respiratory virus, as its target cells range from upper airway respiratory cells to pulmonary cells but also and above all to the cardiovascular cells, such as pericytes and endothelial cells. Indeed, the pathology related to SARS-CoV-2, COVID-19, may be defined as a thromboinflammatory syndrome in its most severe form, characterized by sepsis-induced coagulopathy (SIC) and disseminated intravascular coagulopathy (DIC), which is prevalent in individuals already presenting a chronic level of inflammation (e.g., obese individuals, elderly) and hypertension. Pregnancy is not only an inflammatory-prone condition but is characterized by a consistent rearrangement of the blood circulation and coagulation profile. Cardiac output increases while arterial systolic and diastolic pressure decrease, regardless of the activation of the RAS system. ACE2, the SARS-CoV-2 entry receptor into the host cells, which transforms Ang II in Ang 1–7, is highly expressed in endothelial, smooth muscle cells and pericytes of placental villi, regulating blood pressure and fetal development. Pre-eclampsia is a pregnancy disorder characterized by hypertension and low levels of ACE2, endothelial dysfunction, and a high production of pro-inflammatory cytokines, resembling COVID-19 manifestations. Whereas pre-eclampsia and COVID-19 have overlapping clinical features, a role for SARS-CoV-2 as a leading cause of pre-eclampsia in COVID-19 positive pregnant women has not been clarified yet. In this mini-review, we will explore the possibility of the existence of such a link, focusing on the role of endothelial dysfunction and RAS in both pre-eclampsia and SARS-CoV-2-induced COVID-19 pathogenesis

Cancer metabolism rewiring and chromatin methylation: a vulnerable epi-metabolic link

Over the past few years, significant advances have been made in understanding the crosstalk between cancer metabolism and gene expression. Whereas higher levels of expression of metabolic enzymes may be considered a conceivable compensatory mechanism to satisfy the increasing request of energy of tumor cells, the detection of changes in the amount and species of intermediate metabolites (oncometabolites) and the discovery of their functional role as co-factors and structural components of chromatin modifiers tightened the link between metabolic shifts and epigenome reshaping in cancer. Changes in the chromatin methylation landscape are one of the epigenetic fingerprints of cancer metabolic rewiring associated with the tumorigenic features of neoplasms. Thus, we propose targeting metabolic enzymes directly involved in cancer methylome remodeling and oncometabolite-dependent chromatin modifiers as innovative tools to reset the epigenome of deregulated cancer cells

The COVID-19 legacy: consequences for the human DNA methylome and therapeutic perspectives

The COVID-19 pandemic has left a lasting legacy on human health, extending beyond the acute phase of infection. This article explores the evidence suggesting that SARS-CoV-2 infection can induce persistent epigenetic modifications, particularly in DNA methylation patterns, with potential long-term consequences for individuals’ health and aging trajectories. The review discusses the potential of DNA methylation-based biomarkers, such as epigenetic clocks, to identify individuals at risk for accelerated aging and tailor personalized interventions. Integrating epigenetic clock analysis into clinical management could mark a new era of personalized treatment for COVID-19, possibly helping clinicians to understand patient susceptibility to severe outcomes and establish preventive strategies. Several valuable reviews address the role of epigenetics in infectious diseases, including the Sars-CoV-2 infection. However, this article provides an original overview of the current understanding of the epigenetic dimensions of COVID-19, offering insights into the long-term health implications of the pandemic. While acknowledging the limitations of current data, we emphasize the need for future research to unravel the precise mechanisms underlying COVID-19-induced epigenetic changes and to explore potential approaches to target these modifications

Myc beyond Cancer: Regulation of Mammalian Tissue Regeneration

Myc is one of the most well-known oncogenes driving tumorigenesis in a wide variety of tissues. From the brain to blood, its deregulation derails physiological pathways that grant the correct functioning of the cell. Its action is carried out at the gene expression level, where Myc governs basically every aspect of transcription. Indeed, in addition to its role as a canonical, chromatin-bound transcription factor, Myc rules RNA polymerase II (RNAPII) transcriptional pause–release, elongation and termination and mRNA capping. For this reason, it is evident that minimal perturbations of Myc function mirror malignant cell behavior and, consistently, a large body of literature mainly focuses on Myc malfunctioning. In healthy cells, Myc controls molecular mechanisms involved in pivotal functions, such as cell cycle (and proliferation thereof), apoptosis, metabolism and cell size, angiogenesis, differentiation and stem cell self-renewal. In this latter regard, Myc has been found to also regulate tissue regeneration, a hot topic in the research fields of aging and regenerative medicine. Indeed, Myc appears to have a role in wound healing, in peripheral nerves and in liver, pancreas and even heart recovery. Herein, we discuss the state of the art of Myc’s role in tissue regeneration, giving an overview of its potent action beyond cancer

SARS-CoV-2, Endothelial Dysfunction, and the Renin-Angiotensin System (RAS): A Potentially Dangerous Triad for the Development of Pre-Eclampsia

SARS-CoV-2 represents the greatest epidemiological, clinical, and social challenge the human being has had to face in this century. SARS-CoV-2 is not merely a respiratory virus, as its target cells range from upper airway respiratory cells to pulmonary cells but also and above all to the cardiovascular cells, such as pericytes and endothelial cells. Indeed, the pathology related to SARS-CoV-2, COVID-19, may be defined as a thromboinflammatory syndrome in its most severe form, characterized by sepsis-induced coagulopathy (SIC) and disseminated intravascular coagulopathy (DIC), which is prevalent in individuals already presenting a chronic level of inflammation (e.g., obese individuals, elderly) and hypertension. Pregnancy is not only an inflammatory-prone condition but is characterized by a consistent rearrangement of the blood circulation and coagulation profile. Cardiac output increases while arterial systolic and diastolic pressure decrease, regardless of the activation of the RAS system. ACE2, the SARS-CoV-2 entry receptor into the host cells, which transforms Ang II in Ang 1–7, is highly expressed in endothelial, smooth muscle cells and pericytes of placental villi, regulating blood pressure and fetal development. Pre-eclampsia is a pregnancy disorder characterized by hypertension and low levels of ACE2, endothelial dysfunction, and a high production of pro-inflammatory cytokines, resembling COVID-19 manifestations. Whereas pre-eclampsia and COVID-19 have overlapping clinical features, a role for SARS-CoV-2 as a leading cause of pre-eclampsia in COVID-19 positive pregnant women has not been clarified yet. In this mini-review, we will explore the possibility of the existence of such a link, focusing on the role of endothelial dysfunction and RAS in both pre-eclampsia and SARS-CoV-2-induced COVID-19 pathogenesis.</jats:p

Pillars and Gaps of S-Nitrosylation-Dependent Epigenetic Regulation in Physiology and Cancer

Nitric oxide (NO) is a diffusible signaling molecule produced by three isoforms of nitric oxide synthase, which release NO during the metabolism of the amino acid arginine. NO participates in pathophysiological responses of many different tissues, inducing concentration-dependent effect. Indeed, while low NO levels generally have protective effects, higher NO concentrations induce cytotoxic/cytostatic actions. In recent years, evidences have been accumulated unveiling S-nitrosylation as a major NO-dependent post-translational mechanism ruling gene expression. S-nitrosylation is a reversible, highly regulated phenomenon in which NO reacts with one or few specific cysteine residues of target proteins generating S-nitrosothiols. By inducing this chemical modification, NO might exert epigenetic regulation through direct effects on both DNA and histones as well as through indirect actions affecting the functions of transcription factors and transcriptional co-regulators. In this light, S-nitrosylation may also impact on cancer cell gene expression programs. Indeed, it affects different cell pathways and functions ranging from the impairment of DNA damage repair to the modulation of the activity of signal transduction molecules, oncogenes, tumor suppressors, and chromatin remodelers. Nitrosylation is therefore a versatile tool by which NO might control gene expression programs in health and disease.</jats:p