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HIF2α-Dependent Lipid Storage Promotes Endoplasmic Reticulum Homeostasis in Clear-Cell Renal Cell Carcinoma
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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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“Fatty acid synthesis induced by HIF-2α is crucial for cell viability in ccRCC by sustaining endoplasmic reticulum (ER) homeostasis77.”
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Metadata
- 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
- Venue
- Cancer Discovery
- Published
- 2015-06-01
- Volume
- 5
- Issue
- 6
- Pages
- 652-667
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- 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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