Beyond glycolysis: Hypoxia signaling as a master regulator of alternative metabolic pathways and the implications in clear cell renal cell carcinoma

The relationship between kidney cancer, specifically clear cell renal cell carcinoma (ccRCC), and the hypoxia signaling program has been extensively characterized. Its underlying role as the primary driver of the disease has led to the development of the most effective targeted therapies to date. Cellular responses to hypoxia or mutations affecting the von Hippel-Lindau (VHL) tumor suppressor gene stabilize the hypoxia inducible factor (HIF) transcription factors which then orchestrate elaborate downstream signaling events resulting in adaptations to key biological processes, such as reprogramming metabolism. The direct link of hypoxia signaling to glucose uptake and glycolysis has long been appreciated; however, the HIF family of proteins directly regulate many downstream targets, including other transcription factors with their own extensive networks. In this review, we will summarize our current understanding of how hypoxia signaling regulates other metabolic pathways and how this contributes to the development and progression of clear cell renal cell carcinomas.