SIRT5 is involved in the proliferation and metastasis of breast cancer by promoting aerobic glycolysis

Objective: Breast cancer (BC) is the most commonly diagnosed cancer among females and has a poor prognosis, breast invasive ductal carcinoma is the most common histological type. The occurrence and development of BC is closely related to aberrant glucose metabolism. In the hyperglycemic environment caused by abnormal glucose metabolism, hypoxia-inducible factor-1 alpha (HIF-1 alpha) enables tumor cells to absorb large amounts of glucose and enhance glycolysis by inducing the expression of glucose transporter type1 (GLUT1) and glycolysis genes, thus promoting tumor cell proliferation and metastasis. Mitochondrial Sirtuin5 (SIRT5) plays a role in the rewiring of glucose metabolism during the progression of cancers. Thus, we aimed to elucidate whether SIRT5 promotes BC proliferation and metastasis by facilitating aerobic glycolysis in BC. Methods: The expression of SIRT5 in breast carcinoma tissue and cells was evaluated using immunohistochemical staining, western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis to confirm the biological role of SIRT5 in breast carcinoma. We established a stable cell line with SIRT5 knockdown using lentiviral transduction in T47D cells to reduce SIRT5 expression and then evaluated the effect of SIRT5 on cells cultured in the presence of high glucose (4500 mg/L) and normal glucose (2000 mg/L) concentrations. Cell proliferation was detected using the CCK-8 assay, the cell cycle and cell apoptosis were measured using flow cytometry and Annexin V staining, and cell migration was tested by performing Celigo scratch and Transwell assays. The expression of PKM2, HK2, mTOR and HIF-1 alpha, which play roles in aerobic glycolysis, was investigated using western blot. Results: SIRT5 was overexpressed in BC tissues compared with paired normal tissues. Prognostic and OS analyses showed that the SIRT5 expression level was an individual prognostic factor for patients with BC. SIRT5 knockdown inhibited proliferation and metastasis and slightly increased apoptosis in T47D cells under highglucose conditions. Furthermore, the downregulation of HK2 and HIF-1 alpha caused by SIRT5 knockdown was a high glucose-dependent process, while the downregulation of PKM2 was mediated by a high glucoseindependent process. Conclusions: SIRT5 is an independent prognostic factor for BC and contributes to cell proliferation and metastasis in a high glucose-dependent manner to some degree, which might be mediated by promoting aerobic glycolysis.

Automated summary

SIRT5 expression is associated with prognosis in breast cancer, and it promotes cell proliferation and metastasis through high glucose-dependent aerobic glycolysis.