Clear cell renal cell carcinoma (ccRCC) is characterized by loss of function of the von Hippel-Lindau tumour suppressor (VHL) and unrestrained activation of hypoxia-inducible transcription factors (HIFs). Genetic and epigenetic determinants have an impact on HIF pathways. A recent genome-wide association study on renal cancer susceptibility identified single-nucleotide polymorphisms (SNPs) in an intergenic region located between the oncogenes MYC and PVT1. Here using assays of chromatin conformation, allele-specific chromatin immunoprecipitation and genome editing, we show that HIF binding to this regulatory element is necessary to trans-activate MYC and PVT1 expression specifically in cells of renal tubular origins. Moreover, we demonstrate that the risk-associated polymorphisms increase chromatin accessibility and activity as well as HIF binding to the enhancer. These findings provide further evidence that genetic variation at HIF-binding sites modulates the oncogenic transcriptional output of the VHL-HIF axis and provide a functional explanation for the disease-associated effects of SNPs in ccRCC.
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http://dx.doi.org/10.1038/ncomms13183 | DOI Listing |
Int J Biol Sci
January 2025
Department of Urology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, PR China.
The current research revealed a strong link between lipid reprogramming and dysregulated lipid metabolism to the genesis and development of clear cell renal cell carcinoma (ccRCC). Pathologically, ccRCC exhibits a high concentration of lipid droplets within the cytoplasm. HIF-2α expression has previously been demonstrated to be elevated in ccRCC caused by mutations in the von Hippel-Lindau (VHL) gene, which plays a vital role in the development of renal cell carcinoma.
View Article and Find Full Text PDFSci Rep
January 2025
Shri Dharmasthala Manjunatheshwara (SDM) University, Manjushree Nagar, Sattur, Dharwad, Karnataka, 580009, India.
In oxygen-deprived conditions, cells respond by activating adaptive mechanisms to bolster their survival and protect tissue integrity. A key player in this process is the HIF-1α signaling cascade, meticulously regulated by Prolyl Hydroxylase Domain 2 (PHD2), which orchestrates cellular responses to varying oxygen levels. The primary aim of this investigation is to utilize gut siderophores as inhibitors of PHD2 in ischemic conditions.
View Article and Find Full Text PDFToxics
December 2024
West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
Acute pancreatitis (AP), induced by tetracycline, a widely used antibiotic, poses significant clinical and toxicological challenges, yet its molecular mechanisms remain unclear. This study aims to promote drug toxicology strategies for the effective investigation of the putative toxicity and potential molecular mechanisms of antibiotic drugs through the study of tetracycline in AP. Using the SwissTargetPrediction, SEA Search, Super-PRED, GeneCards, Drugbank, Online Mendelian Inheritance in Man (OMIM), and Therapeutic Target Database (TTD), we identified 259 potential targets associated with tetracycline exposure and AP.
View Article and Find Full Text PDFCancer Sci
January 2025
Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Endometrial cancer (EC) is a worldwide gynecologic malignancies, with a remarking increase of incidence and mortality rates in recent years. Growing evidence indicates that glucose metabolism reprogramming is the most representative metabolic signature of tumor cells and exploring its modulatory function in EC development will promote identifying potential EC therapeutic targets. IGFBP2 is an insulin-like growth factor binding protein which is closely associated with a variety of metabolic diseases.
View Article and Find Full Text PDFToxicol Lett
January 2025
Department of Public Health,International College,Krirk University, Bangkok 10220, Thailand; School of Public Health, Baotou Medical College, Baotou 014030, Inner Mongolia, PR China. Electronic address:
Rare earth is used extensively around the world, and rare earth particles cause a respiratory disease in workers termed rare earth pneumoconiosis(REP) that have attracted considerable attention. However, the mechanisms of REP, characterized by diffuse pulmonary fibrosis, are elusive. REP progression involves various signaling pathway networks comprising numerous cell types and cytokines.
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