Abstract
Tumor tissues are chronically exposed to hypoxia owing to aberrant vascularity. Lipid droplet (LD) accumulation is a hallmark of hypoxic cancer cells, yet how LDs form and function during hypoxia remains poorly understood. Herein, we report that in various cancer cells upon oxygen deprivation, HIF-1 activation down-modulates LD catabolism mediated by adipose triglyceride lipase (ATGL), the key enzyme for intracellular lipolysis. Proteomics and functional analyses identified hypoxia-inducible gene 2 (HIG2), a HIF-1 target, as a new inhibitor of ATGL. Knockout of HIG2 enhanced LD breakdown and fatty acid (FA) oxidation, leading to increased ROS production and apoptosis in hypoxic cancer cells as well as impaired growth of tumor xenografts. All of these effects were reversed by co-ablation of ATGL. Thus, by inhibiting ATGL, HIG2 acts downstream of HIF-1 to sequester FAs in LDs away from the mitochondrial pathways for oxidation and ROS generation, thereby sustaining cancer cell survival in hypoxia.
Highlights
Lipid droplets (LDs) are key organelles responsible for storing cellular surplus of fatty acids (FAs) in esterified forms such as triglycerides (TGs) and sterol esters (Wilfling et al, 2014)
To determine whether lipolytic changes contribute to LD accumulation in hypoxia, we measured free FA release as an index of intracellular lipolysis in various human colorectal cancer (CRC) and renal cell carcinoma (RCC) cell lines under different oxygenated conditions
Consistent with our RCC and CRC cell lines, we found that hypoxia-inducible gene 2 (HIG2) mRNA abundance is strongly associated with various solid tumors including kidney renal clear cell carcinoma (KIRC), colon/rectum adenocarcinoma (COAD/READ), lung squamous cell carcinoma (LUSC), bladder urothelial carcinoma (BLCA), and uterine corpus endometrial carcinoma (UCEC), etc. (Figure 8—figure supplement 1)
Summary
Lipid droplets (LDs) are key organelles responsible for storing cellular surplus of fatty acids (FAs) in esterified forms such as triglycerides (TGs) and sterol esters (Wilfling et al, 2014). While TG-LDs likely form through de novo synthesis of TGs as a lens within the ER bilayer, TG catabolism/lipolysis is catalyzed by LD-localized adipose triglyceride lipase (ATGL) (Zechner et al, 2012). The enzymatic action of ATGL channels hydrolyzed FAs to mitochondria for b-oxidation as well as to the synthesis of lipid ligands for PPARa, whose activation in turn leads to enhanced mitochondrial biogenesis and function. In normal oxidative cell types such as hepatocytes, brown adipocytes and cardiomyocytes, loss of ATGL is known to cause accumulation of TG-LDs and impairment of mitochondrial oxidative capacity (Ahmadian et al, 2011; Haemmerle et al, 2011; Ong et al, 2011). Adipose-specific knockout of ATGL together with HSL causes
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