RESUMO
Cancer cells experiencing hypoxic stress employ epithelial-mesenchymal transition (EMT) to undergo metastasis through rewiring of the chromatin landscape, epigenetics, and importantly, gene expression. Here, we showed that hypoxia modulates the epigenetic landscape on CTCF promoter and upregulates its expression. Hypoxia-driven epigenetic regulation, specifically DNA demethylation mediated by TET2, is a prerequisite for CTCF induction. Mechanistically, in hypoxic conditions, Hypoxia-inducible factor 1-alpha (HIF1α) binds to the unmethylated CTCF promoter, causing transcriptional upregulation. Further, we uncover the pivotal role of CTCF in promoting EMT as loss of CTCF abrogated invasiveness of hypoxic breast cancer cells. These findings highlight the functional contribution of HIF1α-CTCF axis in promoting EMT in hypoxic breast cancer cells. Lastly, CTCF expression is alleviated and the potential for EMT is diminished when the HIF1α binding is particularly disrupted through the dCas9-DNMT3A system-mediated maintenance of DNA methylation on the CTCF promoter. This axis may offer a unique therapeutic target in breast cancer.
Assuntos
Neoplasias da Mama , Fator de Ligação a CCCTC , Hipóxia Celular , Metilação de DNA , Transição Epitelial-Mesenquimal , Subunidade alfa do Fator 1 Induzível por Hipóxia , Regiões Promotoras Genéticas , Humanos , Fator de Ligação a CCCTC/metabolismo , Transição Epitelial-Mesenquimal/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Regiões Promotoras Genéticas/genética , Metilação de DNA/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Dioxigenases , Epigênese Genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , DNA Metiltransferase 3A/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genéticaRESUMO
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.