Monomethyltransferase SETD8 regulates breast cancer metabolism via stabilizing hypoxia-inducible factor 1α.

SETD8 is a methyltransferase that specifically catalyzes the monomethylation of lysine 20 on histone H4. Previous studies have demonstrated that SETD8 is associated with proper cell cycle progression, DNA damage response, and transcriptional regulation. A recent study revealed that SETD8 played an important role in epithelial-mesenchymal transition (EMT) in association with TWIST and enhanced metastatic potential of breast cancer cells. However, the contribution of SETD8 to metabolism reprogramming, one hallmark of cancer, has never been reported. In this study, we report that SETD8 was a positive regulator of anabolic metabolism. SETD8 reprograms breast cancer cell metabolism through hypoxia-inducible factor 1α (HIF1α) mediated process. Mechanistic studies indicated that SETD8 stabilized HIF1α protein level through post-transcriptional regulation. Moreover, we demonstrated that SETD8 was a HIF1α transcription target. In clinical breast cancer patient tissues, we observed a positive correlation of SETD8 with HIF1α and HIF1α target genes. Taken together, we validated SETD8 as a novel metabolic reprogramming regulator, and our mechanistic studies shed light on a novel function of SETD8 in breast cancer malignant properties maintenance.