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

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

Open access
Qiu, Bo, Ackerman, Daniel, Sanchez, Danielle J., Li, Bo, Ochocki, Joshua D., Grazioli, Alison, Bobrovnikova-Marjon, Ekaterina, Diehl, J. Alan +2 more·2015·Cancer Discovery

Published version of a preprint

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

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1158/2159-8290.cd-14-1507

Cites

51 of 51 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Fatty acid synthesis induced by HIF-2α is crucial for cell viability in ccRCC by sustaining endoplasmic reticulum homeostasis.

    “Fatty acid synthesis induced by HIF-2α is crucial for cell viability in ccRCC by sustaining endoplasmic reticulum (ER) homeostasis77.”

    From Glutamine reliance in cell metabolism (2020) · cites this paper as [77]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

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
Venue
Cancer Discovery
Published
2015-06-01
Volume
5
Issue
6
Pages
652-667
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review