Abstract
BackgroundOur previous studies have shown that the E3 ubiquitin ligase of HMG-CoA reductase degradation 1 (HRD1) functions as a tumor suppressor, as overexpression of HRD1 suppressed breast cancer proliferation and invasion. However, its role in breast cancer cell glucose metabolism was unclear. Here, our aim was to uncover the role and molecular mechanisms of HRD1 in regulating aerobic glycolysis in breast cancer.MethodsThe effect of HRD1 on robic glycolysis in breast cancer cells were assessed. Then the proliferation, colony formation ability, invasion and migration of breast cancer cells were evaluated. The relationship between HRD1 and PFKP was validated by Mass spectrometry analysis, immunofluorescence and co-immunoprecipitation. The level of PFKP ubiquitination was measured using ubiquitylation assay. Furthermore, the tumor growth and metastasis in mice xenografts were observed.ResultsWe found that upregulation of HRD1 clearly decreased aerobic glycolysis, and subsequently inhibited breast cancer proliferation and invasion. Mass spectrometry analysis results revealed a large HRD1 interactome, which included PFKP (platelet isoform of phosphofructokinase), a critical enzyme involved in the Warburg Effect in breast cancer. Mechanistically, HRD1 interacted and colocalized with PFKP in the cytoplasm, targeted PFKP for ubiquitination and degradation, and ultimately reduced PFKP expression and activity in breast cancer cells. HRD1 inhibited breast cancer growth and metastasis in vivo through a PFKP-dependent wayConclusionsOur findings reveal a new regulatory role of HRD1 in Warburg effect and provide a key contributor in breast cancer metabolism.Azf-2P6deKCxSLH_gRJtjoVideo abstractGraphic abstract
Highlights
Our previous studies have shown that the E3 ubiquitin ligase of HMG-CoA reductase degradation 1 (HRD1) functions as a tumor suppressor, as overexpression of HRD1 suppressed breast cancer proliferation and invasion
Upregulation of HRD1 led to an obvious decrease in aerobic glycolysis in breast cancer cells The role of HRD1 in breast cancer metabolism was examined by upregulating, HRD1 expression in MCF7 and MDA-MB-231 cells using lentivirus that over-expressed HRD1, as described previously [17]
The resulting breast cancer cells that overexpressed HRD1 exhibited a significant decrease in glucose uptake, while the glucose level was significantly higher in the medium surrounding these cells (Fig. 1a, b)
Summary
Our previous studies have shown that the E3 ubiquitin ligase of HMG-CoA reductase degradation 1 (HRD1) functions as a tumor suppressor, as overexpression of HRD1 suppressed breast cancer proliferation and invasion. Survival, migration, and drug resistance depend on aerobic glycolysis (termed the Warburg Effect), a key feature of energy metabolism that converts glucose into lactate even in the presence of sufficient oxygen [2, 3]. Growing evidence demonstrates that relieving the Warburg effect can be efficacious in inhibiting breast cancer proliferation and invasion [4, 5]. Accumulating evidence has demonstrated that PFKP plays a crucial role in promoting aerobic glycolysis and lactate production in breast cancer cells, thereby stimulating cancer cell proliferation and metastasis [7, 8]. Deletion of PFKP can significantly inhibit lactate production to impair invasion and migration by breast cancer cells [9, 10]. Suppression of PFKP expression and activity represents a viable strategy for breast cancer treatment
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