To determine the Dysgonia stuposa mitochondrial genome (mitogenome) structure and to clarify its phylogenetic position, the entire mitogenome of D. stuposa was sequenced and annotated. The D. stuposa mitogenome is 15,721 bp in size and contains 37 genes (protein-coding genes, transfer RNA genes, ribosomal RNA genes) usually found in lepidopteran mitogenomes. The newly sequenced mitogenome contained some common features reported in other Erebidae species, e.g., an A+T biased nucleotide composition and a non-canonical start codon for cox1 (CGA). Like other insect mitogenomes, the D. stuposa mitogenome had a conserved sequence ‘ATACTAA’ in an intergenic spacer between trnS2 and nad1, and a motif ‘ATAGA’ followed by a 20 bp poly-T stretch in the A+T rich region. Phylogenetic analyses supported D. stuposa as part of the Erebidae family and reconfirmed the monophyly of the subfamilies Arctiinae, Catocalinae and Lymantriinae within Erebidae.
Cholesterol metabolism is highly correlated with risks of pancreatic ductal adenocarcinoma (PDAC). Nevertheless, the underlying mechanisms of activation of cholesterol biogenesis remain inconclusive. KIF11 is a key component of the bipolar spindle and expresses highly in various malignancies. However, its functional role in PDAC tumorigenesis is still unclear. This study aims to elucidate the oncogenic functions of KIF11 in stimulating cholesterol metabolism, thereby driving PDAC progression. We utilized bioinformatics analysis to identify that KIF11 expressed highly in tumor samples versus paired normal tissues and high KIF11 correlated with high clinical stages of patients. Patients with high KIF11 had worse survival outcomes relative to those with low KIF11. Gene set enrichment analysis (GSEA) revealed that KIF11 correlated intensively with the mevalonate (MVA) metabolic pathway. Positive associations were observed between KIF11 and MVA‐signature (HMGCR, FDFT1, SQLE, and MSMO1). KIF11 could elevate the free cholesterol content of PDAC cells and targeting MVA inhibited the in vitro growth of KIF11‐overexpressing cells. Mechanistically, we found KIF11 could interact with SREBP2, the master regulator of MVA. High KIF11 could increase SREBP2 proteins, but not alter their mRNA levels. KIF11 could attenuate the ubiquitination‐mediated degradation of SREBP2, thereby enhancing its stability and accumulation. Accordingly, KIF11 stimulated the expressions of MVA‐signature and free cholesterol contents depending on SREBP2. In addition, KIF11 depended on SREBP2 to promote cell growth, migration, stemness, and colony formation abilities. The subcutaneous xenograft models indicated that targeting MVA biogenesis (atorvastatin) is effective to restrict the in vivo growth of KIF11high PDAC. Taken together, our study identified that KIF11 could activate the MVA cross talk to drive PDAC progression and inhibiting the KIF11/MVA axis provided a therapeutic vulnerability in the treatment of PDAC.
Background:The intensive interplay between aberrant epigenetic events and metabolic remodeling represents one of the hallmarks of tumors, including colon cancer. The functions of Bromodomain Containing Protein BRD-9 in colon cancer remains indefinite. We aimed to identify the biological roles and clinical significance of BRD9 in colon cancer. Methods:The univariate-and multi-variate Cox regression models were used to screen risk epigenetic regulators. Kaplan-Meier analysis and Pearson correlation analysis were used to assess clinical significance of BRD9. CCK-8 assays, colony formation assay, Transwell, and soft-agar assay were performed to determine the in vitro roles of BRD9. The oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of colon cancer cells were evaluated by a Seahorse XF Extracellular Flux Analyzer. In vivo models and RT-qPCR, western blotting, and Chromatin Immunoprecipitation (ChIP) assay were conducted to explore the functional roles of BRD9 in COAD. Results:In the study, we detected the expressions of 662 epigenetic regulators in COAD and identified a series of 42 hazard epigenetic factors with p < 0.05. Lowthroughput MTT assays highlighted that BRD9 is an essential target, and targeting BRD9 could reduce significant decreases of cell growth. BRD9 overexpression could notably elevate proliferation and migration potentialities, whereas, BRD9 ablation abolished these effects. Mechanistically, functional enrichment analysis indicated the potential associations between BRD9 and glycolysis metabolism.In addition, BRD9 epigenetically coordinates the H3K27ac modifications on the promoter regions of ENO2 and ALDOC, inducing enhanced glycolysis activity.Lastly, I-BRD9 could significantly suppress the growth of colon cancer cells in vitro and in vivo.Conclusions: Together, our study revealed previously unidentified roles of BRD9 in colon cancer metabolism and tumor progression, indicating that BRD9 could be a valuable therapeutic target for COAD patients.
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