HIF2α-Dependent Lipid Storage Promotes Endoplasmic Reticulum Homeostasis in Clear-Cell Renal Cell Carcinoma

Abstract

Two hallmarks of clear cell renal cell carcinoma (ccRCC) are constitutive hypoxia inducible factor (HIF) signaling and abundant intracellular lipid droplets (LDs). However, regulation of lipid storage and its role in ccRCC are incompletely understood. Transcriptional profiling of primary ccRCC samples revealed that expression of the LD coat protein gene PLIN2 was elevated in tumors and correlated with HIF-2α, but not HIF-1α, activation. HIF-2α dependent PLIN2 expression promoted lipid storage, proliferation, and viability in xenograft tumors. Mechanistically, lipid storage maintained integrity of the endoplasmic reticulum (ER), which is functionally and physically associated with LDs. Specifically, PLIN2 dependent lipid storage suppressed cytotoxic ER stress responses that otherwise result from elevated protein synthetic activity characteristic of ccRCC cells. Thus, in addition to promoting ccRCC proliferation and anabolic metabolism, HIF-2α modulates lipid storage to sustain ER homeostasis, particularly under conditions of nutrient and oxygen limitation, thereby promoting tumor cell survival.

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

“…We found extensive enhancer gains around well-characterized hypoxia-related targets (ref. 95 51,99). New targets revealed in this study include SMPDL3A, which could be another important ccRCC-specific oncogene given its role in lipid and cholesterol metabolism (61,100).…”

IRE1α RNase–dependent lipid homeostasis promotes survival in Myc-transformed cancers

“…Our results also extend an emerging theme in which oncogenic transformation simultaneously induces anabolic metabolism to increase proliferation along with homeostatic pathways that maintain cell viability. These include lipid and protein scavenging in RAS-transformed tumors (39,53), autophagy downstream of c-Myc overexpression (10), and lipid storage downstream of HIF2α activation (54). The role of the IRE1α/XBP1 pathway in human cancers may be more general, as Genovese et al recently demonstrated that pancreatic ductal adenocarcinoma cells exhibiting a Myc geneexpression signature undergo an anabolic switch that increases protein metabolism and adaptive activation of IRE1α-mediated survival pathways (55).…”

The size matters: regulation of lipid storage by lipid droplet dynamics

“…LDs are also shown to be associated with viral assembly of hepatitis C virus (HCV), dengue virus, bacterial infection, and anti-pathogen infection due to its association with Histone proteins and Viperin (Anand et al, 2012;Camus et al, 2013;Crawford and Desselberger, 2016;D'Avila et al, 2008;Filipe and McLauchlan, 2015;Hinson and Cresswell, 2009). Most recent research has demonstrated that the size of LDs and increased lipid accumulation is associated with cancer development and neural degenerative diseases (Baenke et al, 2013;Chen and Li, 2016;Liu et al, 2015;Qiu et al, 2015).…”