Anti-Warburg effect by targeting HRD1-PFKP pathway may inhibit breast cancer progression

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.

Automated summary

Our study showed that HRD1 overexpression decreased aerobic glycolysis, inhibited breast cancer cell proliferation and invasion. HRD1 interacted with PFKP in the cytoplasm, leading to ubiquitination and degradation of PFKP and ultimately reducing its expression and activity in breast cancer cells. HRD1 suppressed breast cancer growth and metastasis in vivo through a PFKP-dependent mechanism.