Hypoxia, hypoxia-inducible gene 2 (HIG2)/HILPDA, and intracellular lipolysis in cancer

Tumor tissues are chronically exposed to hypoxia owing to aberrant vascularity. Hypoxia induces metabolic alterations in cancer, thereby promoting aggressive malignancy and metastasis. While previous efforts largely focused on adaptive responses in glucose and glutamine metabolism, recent studies have begun to yield important insight into the hypoxic regulation of lipid metabolic reprogramming in cancer. Emerging evidence points to lipid droplet (LD) accumulation as a hallmark of hypoxic cancer cells. One critical underlying mechanism involves the inhibition of adipose triglyceride lipase (ATGL)-mediated intracellular lipolysis by a small protein encoded by hypoxia-inducible gene 2 (HIG2), also known as hypoxia inducible lipid droplet associated (HILPDA). In this review we summarize and discuss recent key findings on hypoxia-dependent regulation of metabolic adaptations especially lipolysis in cancer. We also pose several questions and hypotheses pertaining to the metabolic impact of lipolytic regulation in cancer under hypoxia and during hypoxia-reoxygenation transition.