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

Cancer Discov. 2015 Jun;5(6):652-67. doi: 10.1158/2159-8290.CD-14-1507. Epub 2015 Mar 31.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / pathology
  • Cell Line, Tumor
  • Cell Survival / genetics
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Stress
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Heterografts
  • Homeostasis*
  • Humans
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Lipid Metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Oncogenes
  • Perilipin-2
  • Protein Biosynthesis
  • Tumor Burden
  • Unfolded Protein Response


  • Basic Helix-Loop-Helix Transcription Factors
  • Membrane Proteins
  • PLIN2 protein, human
  • Perilipin-2
  • Plin2 protein, mouse
  • endothelial PAS domain-containing protein 1