Search

The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes major challenges to the healthcare system. SARS-CoV-2 infection leads to millions of deaths worldwide and the mortality rate is found to be greatly associated with pre-existing clinical conditions. The existing dataset strongly suggests that cardiometabolic diseases including hypertension, coronary artery disease, diabetes and obesity serve as strong comorbidities in coronavirus disease (COVID-19). Studies have also shown the poor outcome of COVID-19 in patients associated with angiotensin-converting enzyme-2 polymorphism, cancer chemotherapy, chronic kidney disease, thyroid disorder, or coagulation dysfunction. A severe complication of COVID-19 is mostly seen in people with compromised medical history. SARS-CoV-2 appears to attack the respiratory system causing pneumonia, acute respiratory distress syndrome, which lead to induction of severe systemic inflammation, multi-organ dysfunction, and death mostly in the patients who are associated with pre-existing comorbidity factors. In this article, we highlighted the key comorbidities and a variety of clinical complications associated with COVID-19 for a better understanding of the etiopathogenesis of COVID-19.

Nicotinamide riboside kinase-2 (NRK-2) has recently emerged as a critical regulator of cardiac remodeling however, underlying molecular mechanisms is largely unknown. To explore the same, NRK2 knockout (KO) and littermate control mice were subjected to trans-aortic constriction (TAC) or sham surgeries and cardiac function was assessed by serial M-mode echocardiography. A mild cardiac contractile dysfunction was observed in the KOs at the early adaptive phase of remodeling followed by a significant deterioration during the maladaptive cardiac remodeling phase. Consistently, NRK2 KO hearts displayed increased cardiac hypertrophy and heart failure reflected by morphometric parameters as well as increased fetal genes ANP and BNP expressions. Histological assessment revealed an extensive left ventricular (LV) chamber dilatation accompanied by elevated cardiomyopathy and fibrosis in the KO hearts post-TAC. In a gain-of-function model, NRK-2 overexpressing in AC16 cardiomyocytes displayed significantly attenuated fetal genes ANP and BNP expression. Consistently, NRK-2 overexpression attenuated angiotensin II-induced cardiomyocyte death. Mechanistically, we identified NRK-2 as a regulator of JNK MAP kinase and mitochondrial function where NRK-2 overexpression in human cardiomyocytes markedly suppressed the angiotensin II-induced JNK activation and mitochondrial depolarization. Thus, our results demonstrate that NRK-2 plays protective roles in pressure overload-induced dilatative cardiac remodeling and, genetic ablation exacerbates dilated cardiomyopathy, interstitial collagen deposition, and cardiac dysfunction post-TAC due, in part, to increased JNK activation and mitochondrial dysfunction.

Chromatin remodeling factor metastatic tumor protein 1 (MTA1), one of the most upregulated oncogene in human cancer, has an important role in gene expression, cell survival and promoting hypoxic response. Successful cancer progression is dependent on the ability of cells to utilize its survival pathways for adapting to hypoxic microenvironment. Although MTA1 is a stress-responsive gene, but whether hypoxia modulates its function and its role in engaging other core stress-responsive survival pathway(s) remains unknown. Here we have discovered that MTA1 is a novel corepressor of serum and glucocorticoid-inducible kinase 1 (SGK1). Surprisingly, this regulatory corepressive function of MTA1 is lost under hypoxia, allowing upregulation of SGK1 expression and engaging the MTA1-SGK1 axis for the benefit of the cell survival. The underlying mechanism of the noticed stimulation of SGK1 expression by hypoxia includes de-repression of SGK1 transcription because of hypoxia-triggered nucleus-to-cytoplasmic translocation of MTA1. In addition, the newly recognized cytoplasmic translocation of MTA1 was dependent on the chaperoning function of heat shock protein 90 (HSP90) and co-accompanied by the formation of MTA1, HSP90 and HIF1α complex under hypoxic condition but not under normoxic condition. Hypoxia-triggered redistribution of MTA1, SGK1 upregulation and cell survival functions were compromised by a pharmacological SGK1 inhibitor. In summary, for the first time, we report MTA1 regulation of SGK1 expression, hypoxia-dependent MTA1 translocation to the cytoplasm and de-repression of SGK1 transcription. These findings illustrate how cancer cells utilize a chromatin remodeling factor to engage a core survival pathway to support its cancerous phenotypes, and reveal new facets of MTA1-SGK1 axis by a physiologic signal in cancer progression.

Despite a recognized role of DNA methyltransferase 3a (DNMT3a) in human cancer, the nature of its upstream regulator(s) and relationship with the master chromatin remodeling factor MTA1, continues to be poorly understood. Here, we found an inverse relationship between the levels of MTA1 and DNMT3a in human cancer and that high levels of MTA1 in combination of low DNMT3a status correlates well with poor survival of breast cancer patients. We discovered that MTA1 represses DNMT3a expression via HDAC1/YY1 transcription factor complex. Because IGFBP3 is an established target of DNMT3a, we investigated the effect of MTA1 upon IGFBP3 expression, and found a coactivator role of MTA1/c-Jun/Pol II coactivator complex upon the IGFBP3 transcription. In addition, MTA1 overexpression correlates well with low levels of DNMT3a which, in turn also correlates with a high IGFBP3 status in breast cancer patients and predicts a poor clinical outcome for breast cancer patients. These findings suggest that MTA1 could regulate the expression of IGFBP3 in both DNMT3a-dependent and -independent manner. Together findings presented here recognize an inherent role of MTA1 as a modifier of DNMT3a and IGFBP3 expression, and consequently, the role of MTA1-DNMT3a-IGFBP3 axis in breast cancer progression.

Metastasis-associated protein 1 (MTA1), a component of the nucleosome-remodeling and histone deacetylase complex, is widely up-regulated in human cancers and significantly correlated with tumor invasion and metastasis, but the mechanisms involved remain largely unknown. Here, we report that MTA1 transcriptionally represses the expression of RING finger protein 144A (RNF144A), an uncharacterized gene whose protein product possesses potential E3 ubiquitin ligase activity, by recruiting the histone deacetylase 2 (HDAC2) and CCAAT/enhancer-binding protein α (c/EBPα) co-repressor complex onto human RNF144A promoter. Furthermore, an inverse correlation between the expression levels of MTA1 and RNF144A was demonstrated in publicly available breast cancer microarray datasets and the MCF10 breast cancer progression model system. To address functional aspects of MTA1 regulation of RNF144A, we demonstrate that RNF144A is a novel suppressor of cancer migration and invasion, two requisite steps of metastasis in vivo, and knockdown of endogenous RNF144A by small interfering RNAs accelerates the migration and invasion of MTA1-overexpressing cells. These results suggest that RNF144A is partially responsible for MTA1-mediated migration and invasion and that MTA1 overexpression in highly metastatic cancer cells drives cell migration and invasion by, at least in part, interfering with the suppressive function of RNF144A through transcriptional repression of RNF144A expression. Together, these findings provide novel mechanistic insights into regulation of tumor progression and metastasis by MTA1 and highlight a previously unrecognized role of RNF144A in MTA1-driven cancer cell migration and invasion.

Head and neck cancers usually originate in the squamous cells that line the inner mucosal surfaces of the oral and the neck region. These cancers follow multifocal steps for progression that include risk of developing metastasis. Although therapeutics has advanced in the past decades, head and neck cancers continue to cause much morbidity and mortality. Even with the promising effect of targeted therapies, there is a need for a better evaluation of patients with head and neck cancers. Metastasis-associated tumour antigen 1 (MTA1), a chromatin modifier, is found as an integral part of nucleosome remodelling and histone deacetylation (NuRD) complex. MTA1 is a biomarker for several solid tumours, and the overexpression of which have been documented in various cancers such as breast, ovarian, colon, prostrate etc. Interestingly also, a set of head and neck cancers shows MTA1 overexpression. However, recent evidences from clinical data raise a critical question on the role of MTA1 in head and neck cancers. This calls for a detailed review to the role of MTA1 in oral cancer. This review gives a brief account on the existing biological and molecular data in the context of head and neck cancer invasion and metastasis in relation to MTA1.

Knowledge regarding cervical cancer and human papillomavirus is expanding rapidly. Inflammation subsequent to viral infection is a driving force that accelerates cancer development. The infiltrated immune cells and their secretory cytokines along with chemokines and growth factors greatly contribute the malignant traits of cervical cancer. A better understanding of the mechanisms related to inflammation and cancer progression in terms of pathogen survival, cancer development, progression, and metastasis will lead to innovative approach for treating cancer.