Radiation-induced H3K9 methylation on E-cadherin promoter mediated by ROS/Snail axis : Role of G9a signaling during lung epithelial-mesenchymal transition.

Lung cancer patients who have undergone radiotherapy developed severe complications such as pneumonitis and fibrosis. Upon irradiation, epithelial cells acquire mesenchymal phenotype via a process called epithelial to mesenchymal transition (EMT), which plays a vital role in organ fibrosis. Several mechanisms have been studied on EMT, however, the correlation between radiation-induced EMT and epigenetic changes are not well known. In the present study, we investigated the role of histone methyltransferase G9a on radiation-induced EMT signaling. There was an increase in total global histone methylation level in irradiated epithelial cells. Western blot analysis on irradiated cells showed an increased expression of H3K9me2/3. The pre-treatment of G9a inhibitor enhanced E-cadherin expression and decreased the mesenchymal markers like N-cadherin, vimentin in the radiated group. Surprisingly, radiation-induced ROS generation and pERK1/2 levels were also inhibited by G9a inhibitor BIX01294, which is showing its antioxidant potential. The ChIP-qPCR analysis on the E-cadherin promoter suggested that G9a and Snail might have formed complex to enrich suppressive marker H3K9me2/3. On the whole, our present study suggested that 1] ROS could modify H3K9 methylation via G9a and promote radiation-induced lung EMT in Beas2B and A549 cells 2] E-cadherin promoter enrichment with heterochromatin mark H3K9me2 expression upon irradiation could be modified by regulating G9a methyltransferase.

Literature review on virus and host response proteins in COVID-19: pathobiology, management, diagnosis and treatment.

Coronavirus disease 2019 (COVID-19) is a severe acute respiratory syndrome caused by a novel strain of coronavirus (SARS-CoV-2) which was declared by WHO as a cause of global pandemic. By human-to-human transmission it caused severe damage to mankind with increased mortality rate worldwide. Coronavirus is a spherical enveloped virus with single stranded positive-sense RNA with a size of ~30 kilobases encoding various structural, non-structural and accessory proteins. The entry of coronavirus into the host cells is mediated by spike proteins. SARS-CoV-2 efficiently replicates in host cell and by evading immune surveillance, like innate and adaptive immune responses, in the host cells ultimately leads to increased virulence and disease outcome. In the current review, we highlighted the molecular insights of SARS-CoV-2 and its infection mechanism in the host cell via host-viral protein interactions based on currently available data up to 16thMay 2020 using various research literature databases. The diagnostics of SARS-CoV-2 is mainly done by RT-qPCR and serological tests. There is no effective treatment for COVID-19, however, few methods like plasma therapy and remdesivir treatment are reported to show promising results in improving patient's health and decreasing mortality rate. Keywords: SARS-CoV; spike protein; nucleocapsid; COVID-19; interferon.

The epigenetics of brain tumors and its modulation during radiation: A review.

The brain tumor is the abnormal growth of heterogeneous cells around the central nervous system and spinal cord. Most clinically prominent brain tumors affecting both adult and pediatric are glioblastoma, medulloblastoma, and ependymoma and they are classified according to their origin of tissue. Chemotherapy, radiotherapy, and surgery are important treatments available to date. However, these treatments fail due to multiple reasons, including chemoresistance and radiation resistance of cancer cells. Thus, there is a need of new therapeutic designs to target cell signaling and molecular events which are responsible for this resistance. Recently epigenetic changes received increased attention because it helps in understanding chromatin-mediated disease mechanism. The epigenetic modification alters chromatin structure that affects the docking site of many drugs which cause chemo-resistance of cancer therapy. This review centers the mechanism of how epigenetic changes affect the transcription repression and activation of various genes including Polycomb gene, V-Myc avian myelocytomatosis viral oncogene (MYCN). This review also put forth the pathway of radiation-induced reactive oxygen species generation and its role in epigenetic changes in the cellular level and its impact on tissue physiology. Additionally, there is a strong relationship between the behavior of an individual and environment-induced epigenetic regulation of gene expression. The review also discusses Transcriptome heterogeneity and role of tumor microenvironment in glioblastoma. Overall, this review emphasis important and novel epigenetic targets that could be of therapeutic benefit, which helps in overcoming the unsolved chromatin alteration in brain cancer.

Radiation-Induced Pulmonary Epithelial-Mesenchymal Transition: A Review on Targeting Molecular Pathways and Mediators.

BACKGROUND: Radiotherapy is the most widely used treatment method for average and advanced lung cancer patients. Moreover, the clinical toxicities caused by radiotherapy are categorized into acute radiation pneumonitis and late pulmonary fibrosis. Epithelial-mesenchymal transition (EMT) is a complex physiological process involves many signaling molecules and proteins like adaptor proteins, and transcriptional factors. It was identified as a significant mechanism for fibrosis, wound healing and also cancer. A variety of biomarkers have appeared in radiation-induced lung EMT, some of which are acquired (N-cadherin, vimentin and fibronectin, etc.) and some of which are repressed during the transition of epithelial cells (E-cadherin, zona occludens-1). OBJECTIVE: In the current review, we highlighted the radiation-induced lung EMT signaling pathway and their mediators. We also discuss the EMT in cancer, fibrosis and its epigentics. RESULTS: Radiation-induced lung EMT is controlled by numerous signaling pathways like MAPK, NF-kB, Wnt, microRNAs and histone modifications. Transcriptional factors such as Snail, slug, twist, ZEB1 (Zinc finger E-box binding-1) and ZEB2 (Zinc finger E-box binding-2) proteins are inducers linking radiation-induced EMT and fibrosis. Epigenetic modulations are heritable changes in the structure and function of the genome that occurs without any change in the sequence. Several approaches showed the role of epigenetic modifications and its inhibitors in controlling fibrosis and cancer. Only limited reports are focused on understanding the epigenetic regulations of radiation-induced lung EMT. CONCLUSION: The current review focused on recent findings regarding radiation-induced lung fibrosis and EMT, thus provides some information on important signaling pathways, its subsequent expression of genes and proteins involved in EMT. This review also discussed various inhibitors that could be used to treat EMT related diseases, i.e., fibrosis, cancer.

Effect of Trichostatin A on radiation induced epithelial-mesenchymal transition in A549 cells.

Radiotherapy is used to treat tumors of different origins and nature, but often lead to development of radioresistance and metastasis of cells. Interestingly, radiation induces epithelial-mesenchymal transition (EMT), a process by which epithelial cells undergo mesenchymal phenotype and stimulates tumor progression capability. Our study investigated the effect of Trichostatin A (TSA), a natural derivate isolated from Streptomyces, upon radiation-induced lung EMT and we tried to understand the role of signaling molecules in irradiated lung cancer cells (A549). The cells were categorized into four groups: untreated control, radiation alone (R; 8Gy, X-ray), radiation combined with TSA (R + T) and TSA (100nM). Radiation-induced lung EMT were evidenced by decreased expression of epithelial marker like E-cadherin, Zona occluden1 (ZO-1) and increased expression of N-cadherin and Vimentin. The Snail protein, a master regulator of EMT, was observed to be elevated after radiation treatment. In addition, TGF-ß1 signaling (smad2, 3, and 4) proteins were activated upon irradiation. Western blot data were supported by the altered m-RNA expression of E-cadherin, TGF-ß and Snail genes and this effect were reversed by TSA treatment. In addition to this, as supportive evidence, we performed docking studies between snail protein and TSA using Auto docking software and results suggested that less binding energy was needed for the putative binding of TSA on C-terminal domain of Snail protein. Based on our report, we suggest that TSA can effectively inhibit radiation-induced EMT (i) by altering epithelial and mesenchymal markers (ii) by modulating signaling molecules of TGFß1 pathway (iii) by inhibiting cancer cell migratory potential in A549 cells (iv)by effectively binding to Snail which is an enhancer of EMT.