ANGPTL4 Suppresses Clear Cell Renal Cell Carcinoma via Inhibition of Lysosomal Acid Lipase

Cancer Res Commun. 2024 Aug 1;4(8):2242-2254. doi: 10.1158/2767-9764.CRC-24-0016.

Abstract

Renal cell carcinoma (RCC), the most common form of kidney cancer, is a heterogeneous disease with clear cell RCC (ccRCC) being the most prevalent and aggressive subtype. While most ccRCC tumors have elevated expression of angiopoietin-like4 (ANGPTL4), in our study we identified a significant subset of patients whose cancers show no increase in ANGPTL4 expression. These patients have a worse prognosis compared to the patients with high expression of ANGPTL4. These ANGPTL4-low cancers are characterized by the increased frequency of wild-type Von Hippel-Lindau(WT VHL), a gene that is commonly mutated in ccRCC, and an enrichment for genes associated with lipid metabolism. Using RCC tumor models with WT VHL, we demonstrate that ANGPTL4 behaves as a tumor suppressor. The loss of ANGPTL4 in ccRCC cell lines results in increased tumor growth and colony formation in a lysosomal acid lipase (LAL)-dependent manner, a phenotype rescued by the expression of N-terminus ANGPTL4. At the mechanistic level, the loss of ANGPTL4 increases LAL activity in ccRCC cells. These data suggest that ANGPTL4 enacts its tumor-suppressive effects in ccRCC by regulating LAL activity. Importantly, the identified patient cohort with low ANGPTL4 expression may exhibit increased reliance on lipid metabolism, which can be a point of target for future therapy.

Significance: Our data indicate angiopoietin-like 4 (ANGPTL4) acts as a tumor suppressor in clear cell renal cell carcinoma via regulating lipid metabolism and identifies a cohort of patients with lower expression of ANGPTL4 that are correlated with shorter survival.

Publication types

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

MeSH terms

  • Angiopoietin-Like Protein 4* / genetics
  • Angiopoietin-Like Protein 4* / metabolism
  • Animals
  • Carcinoma, Renal Cell* / genetics
  • Carcinoma, Renal Cell* / metabolism
  • Carcinoma, Renal Cell* / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kidney Neoplasms* / genetics
  • Kidney Neoplasms* / metabolism
  • Kidney Neoplasms* / pathology
  • Mice
  • Prognosis
  • Sterol Esterase* / genetics
  • Sterol Esterase* / metabolism
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism

Substances

  • Angiopoietin-Like Protein 4
  • ANGPTL4 protein, human
  • Sterol Esterase
  • Von Hippel-Lindau Tumor Suppressor Protein
  • LIPA protein, human