SIRT7–SREBP1 restrains cancer cell metabolic reprogramming by upregulating IDH1

Abstract SIRT7 plays critical roles in tumorigenesis and tumor progression; however, the underlying mechanisms are poorly understood. Here, we aimed to identify downstream targets of SIRT7 to help delineate its precise function. In this study, we demonstrate that SIRT7 is essential to regulate IDH1 expression in various cancer cell types. Interestingly, both SIRT7 and IDH1 levels are downregulated in breast cancer lung metastases and are useful for predicting disease progression and prognosis. Mechanistically, SIRT7 enhances IDH1 transcription, and this process is mediated by SREBP1. SIRT7 insufficiency reduces cellular α-ketoglutarate, a metabolite product of IDH1, and suppresses lipogenesis and gluconeogenesis. Moreover, α-ketoglutarate decline increases HIF1α protein levels and, thus, promotes glycolysis. This effect permits cancer cells to facilitate Warburg effect and undergo fast proliferation. Overall, the SIRT7–IDH1 axis regulates cancer cell metabolic reprogramming and, thus, might serve as a point of therapeutic intervention.