Epigenetic Regulation During Hypoxia and Its Implications in Cancer.

Hypoxia is defined as a cellular stress condition caused by a decrease in oxygen below physiologically normal levels. Cells in the core of a rapidly growing solid tumor are faced with the challenge of inadequate supply of oxygen through the blood, owing to improper vasculature inside the tumor. This hypoxic microenvironment inside the tumor initiates a gene expression program that alters numerous signaling pathways, allowing the cancer cell to eventually evade adverse conditions and attain a more aggressive phenotype. A multitude of studies covering diverse aspects of gene regulation has tried to uncover the mechanisms involved in hypoxia-induced tumorigenesis. The role of epigenetics in executing widespread and dynamic changes in gene expression under hypoxia has been gaining an increasing amount of support in recent years. This chapter discusses, in detail, various epigenetic mechanisms driving the cellular response to hypoxia in cancer.

Hypoxia-induced loss of SRSF2-dependent DNA methylation promotes CTCF-mediated alternative splicing of VEGFA in breast cancer.

Alternative splicing of vascular endothelial growth factor A (VEGFA) generates numerous isoforms with unique roles in tumor angiogenesis, and investigating the underlying mechanism during hypoxia necessitates diligent pursuance. Our research systematically demonstrated that the splicing factor SRSF2 causes the inclusion of exon-8b, leading to the formation of the anti-angiogenic VEGFA-165b isoform under normoxic conditions. Additionally, SRSF2 interacts with DNMT3A and maintains methylation on exon-8a, inhibiting CCCTC-binding factor (CTCF) recruitment and RNA polymerase II (pol II) occupancy, causing exon-8a exclusion and decreased expression of pro-angiogenic VEGFA-165a. Conversely, SRSF2 is downregulated by HIF1α-induced miR-222-3p under hypoxic conditions, which prevents exon-8b inclusion and reduces VEGFA-165b expression. Furthermore, reduced SRSF2 under hypoxia promotes hydroxymethylation on exon-8a, increasing CTCF recruitment, pol II occupancy, exon-8a inclusion, and VEGFA-165a expression. Overall, our findings unveil a specialized dual mechanism of VEGFA-165 alternative splicing, instrumented by the cross-talk between SRSF2 and CTCF, which promotes angiogenesis under hypoxic conditions.

PKM2 dictates the poised chromatin state of PFKFB3 promoter to enhance breast cancer progression.

The hypoxic milieu is a critical modulator of aerobic glycolysis, yet the regulatory mechanisms between the key glycolytic enzymes in hypoxic cancer cells are largely unchartered. In particular, the M2 isoform of pyruvate kinase (PKM2), the rate-limiting enzyme of glycolysis, is known to confer adaptive advantages under hypoxia. Herein, we report that non-canonical PKM2 mediates HIF-1α and p300 enrichment at PFKFB3 hypoxia-responsive elements (HREs), causing its upregulation. Consequently, the absence of PKM2 activates an opportunistic occupancy of HIF-2α, along with acquisition of a poised state by PFKFB3 HREs-associated chromatin. This poised nature restricts HIF-2α from inducing PFKFB3 while permitting the maintenance of its basal-level expression by harboring multiple histone modifications. In addition, the clinical relevance of the study has been investigated by demonstrating that Shikonin blocks the nuclear translocation of PKM2 to suppress PFKFB3 expression. Furthermore, TNBC patient-derived organoids and MCF7 cells-derived xenograft tumors in mice exhibited substantial growth inhibition upon shikonin treatment, highlighting the vitality of targeting PKM2. Conclusively, this work provides novel insights into the contributions of PKM2 in modulating hypoxic transcriptome and a previously unreported poised epigenetic strategy exhibited by the hypoxic breast cancer cells for ensuring the maintenance of PFKFB3 expression.

Interplay within tumor microenvironment orchestrates neoplastic RNA metabolism and transcriptome diversity.

The heterogeneous population of cancer cells within a tumor mass interacts intricately with the multifaceted aspects of the surrounding microenvironment. The reciprocal crosstalk between cancer cells and the tumor microenvironment (TME) shapes the cancer pathophysiome in a way that renders it uniquely suited for immune tolerance, angiogenesis, metastasis, and therapy resistance. This dynamic interaction involves a dramatic reconstruction of the transcriptomic landscape of tumors by altering the synthesis, modifications, stability, and processing of gene readouts. In this review, we categorically evaluate the influence of TME components, encompassing a myriad of resident and infiltrating cells, signaling molecules, extracellular vesicles, extracellular matrix, and blood vessels, in orchestrating the cancer-specific metabolism and diversity of both mRNA and noncoding RNA, including micro RNA, long noncoding RNA, circular RNA among others. We also highlight the transcriptomic adaptations in response to the physicochemical idiosyncrasies of TME, which include tumor hypoxia, extracellular acidosis, and osmotic stress. Finally, we provide a nuanced analysis of existing and prospective therapeutics targeting TME to ameliorate cancer-associated RNA metabolism, consequently thwarting the cancer progression. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA Turnover and Surveillance > Regulation of RNA Stability RNA in Disease and Development > RNA in Disease.

Endovascular management of a patient after SAH.

Treatment of acute aneurysmal subarachnoid hemorrhages consists of occluding the aneurysm to prevent rebleed, attempting to prevent vasospasm, and maintaining blood flow to the brain through vessels in vasospasm. Endovascular treatment has been shown to be as safe as, or safer, than surgical clipping for patients with SAH. Engineering solutions to our clinical problems continue to improve endovascular outcomes. This article reviews the current state of endovascular therapy.