Epigenetic Regulation and Post-Translational Modifications of SNAI1 in Cancer Metastasis

SNAI1, a zinc finger transcription factor, not only acts as the master regulator of epithelialmesenchymal transition (EMT) but also functions as a driver of cancer progression, including cell invasion, survival, immune regulation, stem cell properties, and metabolic regulation. The regulation of SNAI1 occurs at the transcriptional, translational, and predominant post-translational levels including phosphorylation, acetylation, and ubiquitination. Here, we discuss the regulation and role of SNAI1 in cancer metastasis, with a particular emphasis on epigenetic regulation and posttranslational modifications. Understanding how signaling networks integrate with SNAI1 in cancer progression will shed new light on the mechanism of tumor metastasis and help develop novel therapeutic strategies against cancer metastasis

The Landscape of Histone Modification in Cancer Metastasis

Metastasis represents one of the most devastating aspects of cancer. Epithelial to mesenchymal transition (EMT) has been shown to play a critical role in tumorigenic metastasis. During metastatic progression, both genetic and epigenetic modifications endow cancer cells with properties that modulate the capacity for metastatic success. Histone modification is profoundly altered in cancer cells and contributes to cancer metastasis by controlling different metastatic phenotypes. Here, we first review histone modifications and discuss their roles in EMT and metastasis, with a particular focus on histone methylation and acetylation. Second, we review the major histone modification enzymes that control chromatin in cancer metastasis. Third, we discuss the transcriptional regulation concerted by these enzymes with EMT transcription factors at different molecular layers. Finally, we discuss pharmacologic manipulation of histone modification enzymes for metastasis treatment. A comprehensive understanding of histone modification in metastasis will not only provide new insights into our knowledge of cancer progression and metastasis, but also offer a novel approach for the development of innovative therapeutic strategies

Ubiquitin Regulation: The Histone Modifying Enzyme\u27s Story

Histone post-translational modifications influence many fundamental cellular events by regulating chromatin structure and gene transcriptional activity. These modifications are highly dynamic and tightly controlled, with many enzymes devoted to the addition and removal of these modifications. Interestingly, these modifying enzymes are themselves fine-tuned and precisely regulated at the level of protein turnover by ubiquitin-proteasomal processing. Here, we focus on recent progress centered on the mechanisms regulating ubiquitination of histone modifying enzymes, including ubiquitin proteasomal degradation and the reverse process of deubiquitination. We will also discuss the potential pathophysiological significance of these processes

Tackle Epithelial-Mesenchymal Transition with Epigenetic Drugs in Cancer

Epithelial-mesenchymal Transition (EMT) is a de-differentiation process in which epithelial cells lose their epithelial properties to acquire mesenchymal features. EMT is essential for embryogenesis and wound healing but is aberrantly activated in pathological conditions like fibrosis and cancer. Tumor-associated EMT contributes to cancer cell initiation, invasion, metastasis, drug resistance and recurrence. This dynamic and reversible event is governed by EMT-transcription factors (EMT-TFs) with epigenetic complexes. In this review, we discuss recent advances regarding the mechanisms that modulate EMT in the context of epigenetic regulation, with emphasis on epigenetic drugs, such as DNA demethylating reagents, inhibitors of histone modifiers and non-coding RNA medication. Therapeutic contributions that improve epigenetic regulation of EMT will translate the clinical manifestation as treating cancer progression more efficiently

The Regulation of Snail: On the Ubiquitin Edge

Metastasis accounts for a majority of cancer death. One key feature during metastasis is epithelial-mesenchymal transition (EMT), which is regulated by transcription factors such as Snail and Twist. In non-malignant cells, Snail has a short half-life and is degraded via ubiquitination, but its stability is increased in cancer cell. However, the mechanism by which Snail escapes ubiquitination and degradation remains unknown. Recently, we found that Dub3 is a deubiquinase of Snail. Most importantly, we determined that Dub3 responded to extracellular signals such as IL-6, and that the resultant signaling prevented Snail degradation, and promoted cancer growth, invasion, and migration. In this highlight, we present a concise picture of how the transcription factor Snail is regulated by ubiquitination in cancer cells, the role of Dub3 in this process, and its potential use as a treatment target

Age-related sensitivity and pathological differences in infections by 2009 pandemic influenza A (H1N1) virus

<p>Abstract</p> <p>Background</p> <p>The highly pandemic 2009 influenza A H1N1 virus infection showed distinguished skewed age distribution with majority of infection and death in children and young adults. Although previous exposure to related antigen has been proposed as an explanation, the mechanism of age protection is still unknown.</p> <p>Methods</p> <p>In this study, murine model of different ages were inoculated intranasally with H1N1 (A/Beijing/501/09) virus and the susceptibility and pathological response to 2009 H1N1 infection were investigated.</p> <p>Results</p> <p>Our results showed that the younger mice had higher mortality rate when infected with the same dose of virus and the lethal dose increased with age. Immunohistochemical staining of H1N1 antigens in mice lung indicated infection was in the lower respiratory tract. Most bronchial and bronchiolar epithelial cells in 4-week mice were infected while only a minor percentage of those cells in 6-month and 1-year old mice did. The young mice developed much more severe lung lesions and had higher virus load in lung than the two older groups of mice while older mice formed more inducible bronchus-associated lymphoid tissue in their lungs and more severe damage in spleen.</p> <p>Conclusions</p> <p>These results suggest that young individuals are more sensitive to H1N1 infection and have less protective immune responses than older adults. The age factor should be considered when studying the pathogenesis and transmission of influenza virus and formulating strategies on vaccination and treatment.</p

Application of extracorporeal membrane oxygenation to adults with cardiogenic shock and cardiac arrest in hospital

Objective·To assess the effect of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) treatment on the mortality rate of patients suffering from cardiogenic shock and cardiac arrest in hospital.Methods·A total of 19 patients with cardiogenic shock or cardiac arrest who were treated with VA-ECMO treatment in Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine from September 2017 to March 2022 were included in the retrospective study. Patients were divided into extracorporeal cardiopulmonary resuscitation (ECPR) group (n=9) and VA-ECMO for cardiogenic shock (E-CS) group (n=10) according to whether cardiac arrest had occurred. The general demographic data, clinical data, Sequential Organ Failure Assessment (SOFA) scores, postoperative complications and prognostic indicators of the two groups of patients were collected. Univariate and multivariate Cox proportional hazard regression analyses were used to evaluate the correlation between each covariate and hospital mortality.Results·Among the included patients, there were 15 males (78.9%), with an average age of 46.5 (34.5, 61.6) years. The incidence of postoperative complications was as follows: bleeding (47.4%), AKI (36.8%), infection (31.6%), limb ischemia (15.8%) and cerebrovascular accident (5.3%). The duration of VA-ECMO was 4.0 (2.0, 6.8) days, and the intensive care duration was 11.5 (5.8, 26.2) days; the ECMO withdrawal success rate was 63.2%, and the hospital mortality was 63.2%. The results of univariate Cox proportional hazard regression analysis showed that AKI (prior to VA-ECMO initiation), postoperative complications of infection and limb ischemia were correlated with the hospital mortality of patients (all P<0.05). The results of multivariate Cox proportional hazard regression analysis showed that AKI (prior to VA-ECMO initiation), postoperative complications of infection and limb ischemia were also independent risk factors for the hospital mortality of patients (all P<0.05).Conclusion·For patients with cardiogenic shock and cardiac arrest treated with VA-ECMO, AKI (prior to VA-ECMO initiation), postoperative infection and limb ischemia are independently associated with higher hospital mortality