No abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, employs two key host proteins to gain entry and replicate within cells, angiotensin-converting enzyme 2 (ACE2) and the cell surface transmembrane protease serine 2 (TMPRSS2). TMPRSS2 was first characterized as an androgen-regulated gene in the prostate. Supporting a role for sex hormones, males relative to females are disproportionately affected by COVID-19 in terms of mortality and morbidity. Several studies, including one employing a large epidemiological cohort, suggested that blocking androgen signaling is protective against COVID-19. Here, we demonstrate that androgens regulate the expression of ACE2, TMPRSS2, and androgen receptor (AR) in subsets of lung epithelial cells. AR levels are markedly elevated in males relative to females greater than 70 y of age. In males greater than 70 y old, smoking was associated with elevated levels of AR and ACE2 in lung epithelial cells. Transcriptional repression of the AR enhanceosome with AR or bromodomain and extraterminal domain (BET) antagonists inhibited SARS-CoV-2 infection in vitro. Taken together, these studies support further investigation of transcriptional inhibition of critical host factors in the treatment or prevention of COVID-19.

Diverse subtypes of renal cell carcinomas (RCCs) display a wide spectrum of histomorphologies, proteogenomic alterations, immune cell infiltration patterns, and clinical behavior. Delineating the cells of origin for different RCC subtypes will provide mechanistic insights into their diverse pathobiology. Here, we employed single-cell RNA sequencing (scRNA-seq) to develop benign and malignant renal cell atlases. Using a random forest model trained on this cell atlas, we predicted the putative cell of origin for more than 10 RCC subtypes. scRNA-seq also revealed several attributes of the tumor microenvironment in the most common subtype of kidney cancer, clear cell RCC (ccRCC). We elucidated an active role for tumor epithelia in promoting immune cell infiltration, potentially explaining why ccRCC responds to immune checkpoint inhibitors, despite having a low neoantigen burden. In addition, we characterized an association between high endothelial cell types and lack of response to immunotherapy in ccRCC. Taken together, these single-cell analyses of benign kidney and RCC provide insight into the putative cell of origin for RCC subtypes and highlight the important role of the tumor microenvironment in influencing ccRCC biology and response to therapy.

SignificanceRecent advances in cancer epigenetics have shown the involvement of epigenetic abnormalities in the initiation and progression of cancer, but their role in cancer-specific aberrant splicing is not clear. The identification of upstream epigenetic regulators of cancer-specific splicing will enable us to therapeutically target aberrant splicing and provide an approach to cancer therapy. Here we have demonstrated a mechanism of intragenic DNA methylation-mediated regulation of alternative splicing by Brother of Regulator of Imprinted Sites (BORIS), which can contribute to breast cancer tumorigenesis by favoring the Warburg effect. The reversal of the Warburg effect was achieved by the inhibition of DNA methylation or down-regulation of BORIS, which may serve as a useful approach to inhibit the growth of breast cancer cells.

No abstract

The discovery of an increasing number of alternative splicing events in the human genome highlighted that ∼94% of genes generate alternatively spliced transcripts that may produce different protein isoforms with diverse functions. It is now well known that several diseases are a direct and indirect consequence of aberrant splicing events in humans. In addition to the conventional mode of alternative splicing regulation by '' RNA-binding sites and ' RNA-binding proteins, recent literature provides enormous evidence for epigenetic regulation of alternative splicing. The epigenetic modifications may regulate alternative splicing by either influencing the transcription elongation rate of RNA polymerase II or by recruiting a specific splicing regulator via different chromatin adaptors. The epigenetic alterations and aberrant alternative splicing are known to be associated with various diseases individually, but this review discusses/highlights the latest literature on the role of epigenetic alterations in the regulation of alternative splicing and thereby cancer progression. This review also points out the need for further studies to understand the interplay between epigenetic modifications and aberrant alternative splicing in cancer progression.

The histone demethylase KDM1A specifically demethylates lysine residues and its deregulation has been implicated in the initiation and progression of various cancers. However, KDM1A's molecular role and its pathological consequences, and prognostic significance in oral cancer remain less understood. In the present study, we sought to investigate the expression of KDM1A and its downstream role in oral cancer pathogenesis. By comparing mRNA expression profiles, we identified an elevated KDM1A expression in oral tumors when compared to normal oral tissues. In silico pathway prediction identified the association between KDM1A and E2F1 signaling in oral cancer. Pathway scanning, functional annotation analysis and In vitro assays showed the KDM1A's involvement in oral cancer cell proliferation and the cell cycle. Moreover, real time PCR and luciferase assays confirmed KDM1A's role in regulation of E2F1 signaling activity in oral cancer. Elevated KDM1A expression is associated with poor clinical outcome in oral cancer. Our data indicate that deregulated KDM1A expression is positively associated with proliferative phenotype of oral cancer and confers poor clinical outcome. These cumulative data suggest that KDM1A might be a potential diagnostic and therapeutic target for oral cancer.

The tumor microenvironment is marked by gradients in the level of oxygen and nutrients, with oxygen levels reaching a minimum at the core of the tumor, a condition known as tumor hypoxia. Mediated by members of the HIF family of transcription factors, hypoxia leads to a more aggressive tumor phenotype by transactivation of several genes as well as reprogramming of pre-mRNA splicing. Intragenic DNA methylation, which is known to affect alternative splicing in cancer, could be one of several reasons behind the changes in splicing patterns under hypoxia.Here, we have tried to establish a correlation between intragenic DNA methylation and alternative usage of exons in tumor hypoxia. First, we have generated a custom hypoxia signature consisting of 34 genes that are up-regulated under hypoxia and are direct targets of HIF-1α. Using this gene expression signature, we have successfully stratified publicly available breast cancer patient samples into hypoxia positive and hypoxia negative groups followed by mining of differentially spliced isoforms between these groups. The Hypoxia Hallmark signature from MSigDB was also used independently to stratify the same tumor samples into hypoxic and normoxic. We found that 821 genes were showing differential splicing between samples stratified using a custom signature, whereas, 911 genes were showing differential splicing between samples stratified using the MSigDB signature. Finally, we performed multiple correlation tests between the methylation levels (α) of microarray probes located within 1 kilo base pairs of isoform-specific exons using those exons' expression levels in the same patient samples in which the methylation level was recorded. We found that the expression level of one of the exons of DHX32 and BICD2 significantly correlated with the methylation levels, and we were also able to predict patient survival (p-value: 0.02 for DHX32 and 0.0024 for BICD2). Our findings provide new insights into the potential functional role of intragenic DNA methylation in modulating alternative splicing during hypoxia.