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

• Published in: Cancer letters Vol. 493; pp. 71 - 79
• Main Authors: Povero, Davide, Johnson, Scott M., Liu, Jun
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28.11.2020; Elsevier Limited
• Subjects: Adaptation; Angiogenesis; ATGL; Biosynthesis; Cancer; Cell growth; Dehydrogenases; Down-Regulation; Drug resistance; Enzymes; Fatty acid; Fatty acids; Gene expression; Gene Expression Regulation, Neoplastic; Glucose; Glucose metabolism; Glutamine; HIF; HIG2; HILPDA; Homeostasis; Humans; Hypoxia; Hypoxia inducible gene 2; Hypoxia-inducible factor; Intracellular; Kinases; Lipase; Lipase - metabolism; Lipid droplet; Lipid Droplets - metabolism; Lipid metabolism; Lipids; Lipolysis; Liver cancer; Malignancy; Metabolism; Metastases; Metastasis; Mutation; Neoplasm Proteins - metabolism; Neoplasms - metabolism; Oxidation; Oxidative stress; Oxygen; Proteins; Tumor Hypoxia; Tumors; Oxygen; Lipid droplet; HIF; Fatty acid; ATGL; HILPDA; Hypoxia-inducible factor; Hypoxia; HIG2; Lipolysis; Hypoxia inducible gene 2
• ISSN: 0304-3835; 1872-7980; 1872-7980
• DOI: 10.1016/j.canlet.2020.06.013

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. •Hypoxia induces metabolic remodeling in solid tumors.•Hypoxia promotes lipid droplet (LD) accumulation through inhibition of lipolysiscatalyzed by adipose triglyceride lipase (ATGL).•Hypoxia inducible gene 2 (HIG2) is a specific inhibitor of ATGL.•The review covers function of HIG2 as a key regulator of hypoxic cancer cell survival.•Targeting HIG2-ATGL interaction should be considered in the future.