RESUMO
Recent studies have shed light on disrupted collagen signaling in Gliomas, yet the regulatory landscape remains largely unexplored. This study enquired into the role of polycomb repressive complex-2 (PRC2)-mediated H3K27me3 modification, a key epigenetic factor in glioma. Using in-house data, we identified miRNAs downregulated in glioblastoma (GBM) with the potential to regulate Collagen VI family genes. Notably, miR-3189 emerged as a prime PRC2 target. Its expression was significantly downregulated in Indian GBM patients as well as other glioma cohorts. Mechanistic insights, involving Luciferase assays, mutagenesis, and Western blot analysis, confirmed direct targeting of Collagen VI member COL6A2 by miR-3189-3p. Functional assays demonstrated that miR-3189-3p restrained GBM malignancy by inhibiting proliferation, migration, and epithelial-mesenchymal transition (EMT). Conversely, COL6A2 overexpressed in GBM patients, countered miR-3189, and promoted the malignant phenotype. Gene set enrichment analysis highlighted EMT enrichment in GBM patients with elevated COL6A2 expression, carrying prognostic implications. This study uncovers intricate interactions between two epigenetic regulators-H3K27me3 and miR-3189-working synergistically to modulate Collagen VI gene; thus, influencing the malignancy of GBM. Targeting this H3K27me3|miR-3189-3p|COL6A2 axis presents a potential therapeutic avenue against GBM.
Assuntos
Movimento Celular , Proliferação de Células , Colágeno Tipo VI , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Glioblastoma , MicroRNAs , Complexo Repressor Polycomb 2 , Humanos , Transição Epitelial-Mesenquimal/genética , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Colágeno Tipo VI/genética , Colágeno Tipo VI/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Movimento Celular/genética , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Epigênese Genética/genéticaRESUMO
Glioblastoma (GBM) is the most aggressive cancer of central nervous system with worst patient outcome. Telomere maintenance is a crucial mechanism governing GBM initiation and progression making it an attractive target. microRNAs (miRNAs) have shown therapeutic potential in GBM. Earlier, we showed miR-490 is downregulated in GBM patients and plays a tumor suppressive role. Here, we show that miR-490 regulates telomere maintenance program in GBM by directly targeting Telomeric Repeat-binding Factor 2 (TERF2) of the shelterin complex, Tankyrase 2 (TNKS2) and Serine/Threonine-protein kinase, SMG1. Overexpression of miR-490 resulted in effects characteristic to hampered telomere maintenance via TERF2 inhibition. These include induction of telomere dysfunction-induced foci and global DNA damage (53BP1 foci), along with an increase in p-γH2AX levels. Further, it led to inhibition of telomere maintenance hallmarks via reduced stemness (SOX2 and SOX4 downregulation) and induction of senescence (H3K9me3 marks gain and SIRT1 downregulation). It also initiated downstream DNA damage response (DDR) leading to p53 pathway activation. Moreover, microarray data analysis highlighted an overlap between miR-490 expression and REST-inhibition responses in GBM. Thus, miR-490-mediated targeting of telomere maintenance could be therapeutically important in GBM.
Assuntos
Neoplasias Encefálicas/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , MicroRNAs/genética , Homeostase do Telômero/genética , Regiões 3' não Traduzidas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo , Tanquirases/genética , Tanquirases/metabolismo , Proteína 2 de Ligação a Repetições Teloméricas/genética , Proteína 2 de Ligação a Repetições Teloméricas/metabolismoRESUMO
MicroRNAs (miRNAs) are small non-coding RNAs that function as posttranscriptional gene regulators. Among a pool of >2600 known human mature miRNAs, only a small subset have been functionally interrogated and a further smaller pool shown to be associated with the pathogenesis of a variety of diseases suggesting their critical role in maintaining homeostasis. Here, we draw your attention to one such miRNA, miR-490, that has been reported to be deregulated in a myriad of diseases (23 diseases) ranging from cardiomyopathy, depression, and developmental disorders to many cancer types (28 cancer types), such as hepatocellular carcinoma, gastric cancer, cancers of the reproductive and central nervous system among others. The prognostic and diagnostic potential of miR-490 has been reported in many diseases including cancer underlining its clinical relevance. We also collate a complex plethora of epigenetic (histone and DNA methylation), transcriptional (TF), and posttranscriptional (lncRNA and circRNA) mechanisms that have been shown to tightly regulate miR-490 levels. The targets of miR-490 involve a range of cancer-related genes involved in the regulation of various cancer hallmarks like cell proliferation, migration, and invasion, apoptotic cell death, angiogenesis, and so forth. Overall, our in-depth review highlights for the first time the emerging role of miR-490 in disease pathology, diagnosis, and prognosis that assigns a unique therapeutic potential to miR-490 in the era of precision medicine.
Assuntos
Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Biomarcadores Tumorais/genética , Proliferação de Células/genética , HumanosRESUMO
Glioblastoma multiforme (GBM) encompasses brain malignancies marked by phenotypic and transcriptional heterogeneity thought to render these tumors aggressive, resistant to therapy, and inevitably recurrent. However, little is known about how the spatial organization of GBM genomes underlies this heterogeneity and its effects. Here, we compile a cohort of 28 patient-derived glioblastoma stem cell-like lines (GSCs) known to reflect the properties of their tumor-of-origin; six of these were primary-relapse tumor pairs from the same patient. We generate and analyze 5 kbp-resolution chromosome conformation capture (Hi-C) data from all GSCs to systematically map thousands of standalone and complex structural variants (SVs) and the multitude of neoloops arising as a result. By combining Hi-C, histone modification, and gene expression data with chromatin folding simulations, we explain how the pervasive, uneven, and idiosyncratic occurrence of neoloops sustains tumor-specific transcriptional programs via the formation of new enhancer-promoter contacts. We also show how even moderately recurrent neoloops can relate to patient-specific vulnerabilities. Together, our data provide a resource for dissecting GBM biology and heterogeneity, as well as for informing therapeutic approaches.