Cited by 400Cancer, Lipids, and MetabolismCancer, Hypoxia, and MetabolismLipid metabolism and biosynthesis

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

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Qiu, Bo, Ackerman, Daniel, Sanchez, Danielle J., Li, Bo, Ochocki, Joshua D., Grazioli, Alison, Bobrovnikova-Marjon, Ekaterina, Diehl, J. Alan, Keith, Brian, Simon, M. Celeste·2015·Cancer Discovery

DOI 10.1158/2159-8290.cd-14-1507PMC PMC4456212

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Abstract

Two hallmarks of clear-cell renal cell carcinoma (ccRCC) are constitutive hypoxia-inducible factor (HIF) signaling and abundant intracellular lipid droplets (LD). 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 HIF2α, but not HIF1α, activation. HIF2α-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, HIF2α modulates lipid storage to sustain ER homeostasis, particularly under conditions of nutrient and oxygen limitation, thereby promoting tumor cell survival. Significance: We demonstrate that HIF2α promotes lipid storage, ER homeostasis, and cell viability in ccRCC via upregulation of the LD coat protein PLIN2, revealing a novel function for the well-documented “clear-cell” phenotype and identifying ER stress as a targetable vulnerability created by HIF2α/PLIN2 suppression in this common renal malignancy. Cancer Discov; 5(6); 652–67. ©2015 AACR. See related commentary by Sim and Johnson, p. 584. This article is highlighted in the In This Issue feature, p. 565

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Authors: Qiu, B., Ackerman, D., Sanchez, D. J., Li, B., Ochocki, J. D., Grazioli, A., Bobrovnikova-Marjon, E., Diehl, J. A., Keith, B., & Simon, M. C.
Affiliations: University of Pennsylvania (US)
Medical University of South Carolina (US)
Howard Hughes Medical Institute (US)
Corresponding author: Simon, M. Celeste
ORCID: Qiu, Bo
Ackerman, Daniel
Sanchez, Danielle J.
Li, Bo
Grazioli, Alison
Diehl, J. Alan
Keith, Brian
Simon, M. Celeste
Venue: Cancer Discovery
Publisher: American Association for Cancer Research (AACR)
Published: 2015-06-01
Volume: 5
Issue: 6
Pages: 652-667
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-14-1507
PMC: PMC4456212
OpenAlex: W2135546443
Cited by: 394
References: 51
Citations by year: 2026: 27 · 2025: 37 · 2024: 69 · 2023: 32 · 2022: 47 · 2021: 47 · 2020: 38 · 2019: 27 · 2018: 29 · 2017: 22 · 2016: 14 · 2015: 4
FWCI: 7.60
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Cancer Discovery (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Howard Hughes Medical Institute
National Cancer Institute (F30CA177106, 2-P01-CA104838, P01CA104838, 5-F30-CA177106, F32CA192758)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD083185)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords: HIF-2α, clear cell renal cell carcinoma, lipid droplets, PLIN2, endoplasmic reticulum homeostasis, endoplasmic reticulum stress, fat deposition, tumor hypoxia, tumor cell survival
MeSH terms: Perilipin-2, Endothelial PAS Domain-Containing Protein 1, Animals, Carcinoma, Renal Cell, Cell Survival, Disease Models, Animal, Endoplasmic Reticulum, Homeostasis, Humans, Kidney Neoplasms, Membrane Proteins, Oncogenes, Protein Biosynthesis, Gene Expression, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, Cell Line, Tumor, Tumor Burden, Lipid Metabolism, Mice, Basic Helix-Loop-Helix Proteins, Unfolded Protein Response, Endoplasmic Reticulum Stress, Heterografts

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

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