BackgroundGlycolysis plays a pivotal role in breast cancer stem-like cell reprogramming. The SET-domain containing 5 (SETD5) is a previously uncharacterized member of the histone lysine methyltransferase family. Yet, the molecular mechanisms underlying the promotion of stem-like and glycolysis activation traits of SETD5 have not been elucidated.MethodsBasing on public datasets, we explored clinicopathological and survival analysis of SETD5 on breast cancer (BC) patients. Spheroid formation, transfection experiments and measurement of glucose uptake and lactate production analyzed the regulatory function of SETD5 on glycolysis in breast cancer stem-like cells (BCSC). The impact of SETD5 on tumor growth was studied in a murine xenograft model. Immunohistochemistry, immunofluorescence, western blot, preparation of cytoplasmic and nuclear extracts and co-immunoprecipitation were used to determine the molecular mechanisms of SETD5 in cancer cell glycolysis.ResultsOur data displayed that overexpression of SETD5 in BC tissues is positively associated with progression. SETD5 overexpression is associated with poor post-progression survival in BC patients. SETD5 expression was enriched in spheroid cells. Downregulation of SETD5 significantly decreased BCSC properties and glycolysis in vitro and in vivo. Interestingly, SETD5 and glycolytic enzymes were accumulated in the central hypoxic regions of subcutaneous tumor tissues. Our mechanistic study found that SETD5 binding to EP300/hypoxia-inducible factor 1α (HIF1α) and work as an upstream effector. SETD5 knockdown reduced the expression of HIF1α, hexokinase-2, and 6-phosphofructo-2-kinase in the nucleus after treatment with cobalt chloride (CoCl2), a chemical hypoxia mimetic agent, which activates HIF1α to accumulate in the nucleus. ConclusionSETD5 is required for glycolysis in BCSCs through binding to EP300/HIF1α and could be a potential therapeutic target for BC patients.
