The anti‐angiogenesis role of FBXW7 in diabetic retinopathy by facilitating the ubiquitination degradation of c‐Myc to orchestrate the HDAC2

Abstract

Diabetic retinopathy (DR) is the most prevalently occurring microvascular complication in diabetic patients that triggers severe visual impairments. The anti‐angiogenesis role of FBXW7 has been identified in breast cancer. Therefore, this study intends to decipher the mechanism of FBXW7 in angiogenesis of DR. DR model was induced on mice using high‐glucose (HG) and high‐fat diet, and retinal microvascular endothelial cells (RMECs) isolated from normal mice were induced with HG, followed by evaluation of FBXW7, Ki67, HIF‐1α and VEGF expression by immunofluorescence, immunohistochemistry or Western blot analysis. After gain‐ and loss‐of‐function assays in normal and DR mice, angiogenesis was assessed by CD31 fluorescence staining and Western blot analysis. After ectopic expression and silencing experiments in HG‐induced RMECs, RMEC proliferation, migration and angiogenesis were, respectively, determined by EdU, Transwell and in vitro angiogenesis assays. The impact of FBXW7 on the ubiquitination of c‐Myc was studied by cycloheximide chase assay and proteasome inhibition, and the binding of c‐Myc to HDAC2 promoter by dual‐luciferase reporter gene experiment. DR mice and HG‐induced RMECs possessed down‐regulated FBXW7 and up‐regulated Ki67, HIF‐1α and VEGF. Silencing FBXW7 enhanced angiogenesis in normal mouse retinal tissue, but overexpressing FBXW7 or silencing c‐Myc diminished angiogenesis in DR mouse retinal tissue. Overexpressing FBXW7 or silencing c‐Myc depressed proliferation, migration and angiogenesis in HG‐induced RMECs. FBXW7 induced c‐Myc ubiquitination degradation, and c‐Myc augmented HDAC2 expression by binding to HDAC2 promoter. Conclusively, our data provided a novel sight of anti‐angiogenesis role of FBXW7 in DR by modulating the c‐Myc/HDAC2 axis.

FBXW7 inhibits the Progression of ESCC by directly inhibiting the Stemness of Tumor Cells

“…Our results revealed that FBXW7 might be a considerable factor in angiogenesis, DNA damage and cell senescence pathway, forming a complex regulatory network and playing an important role in ESCC. Corroborate with our ndings, Lihua Hu's study have shown that FBXW7 overexpression reduces angiogenesis in retinal tissues of mice with diabetic retinopathy [47]. Therefore, we applied the vascular mimicry experiments to determine the the effect of FBXW7 on angiogenesis of ESCC cells, and realized that FBXW7 could inhibited the angiogenesis ability of ESCC cells.…”

Extracellular matrix derived from Wharton’s Jelly-derived mesenchymal stem cells promotes angiogenesis via integrin αVβ3/c-Myc/P300/VEGF

“…2 a, b, g, h, P < 0.05 or P < 0.01). The transcription factor c-Myc regulates the expression of several key genes related to angiogenesis [ 22 – 24 ]. Next, to find out whether c-Myc was involved in the increased expression of VEGF induced by WJ-MSCs ECM, we examined the effects of WJ-MSCs ECM on the expression of c-Myc.…”

HDAC10 Inhibits Cervical Cancer Progression through Downregulating the HDAC10-microRNA-223-EPB41L3 Axis

“…These results are in accordance with the conclusions from recent studies that HDAC acts as a regulator in tumor via changing the nucleosome conformation of tumor cells. It is well acknowledged that HADC participates in cellular modulation in various cells by regulating miRNAs, for example, HDAC2 regulates miR-503-5p in esophageal squamous cell carcinoma [ 35 ], HDAC2 promotes the endothelial dysfunction induced by diabetes [ 36 , 37 ], and HDACs regulate the cellular differentiation in neurodegenerative diseases [ 38 ].…”