NKX2-8 deletion-induced reprogramming of fatty acid metabolism confers chemoresistance in epithelial ovarian cancer

EBioMedicine. 2019 May;43:238-252. doi: 10.1016/j.ebiom.2019.04.041. Epub 2019 Apr 29.

Abstract

Background: Aberrant fatty acid (FA) metabolism is a unique vulnerability of cancer cells and may present a promising target for cancer therapy. Our study aims to elucidate the molecular mechanisms by which NKX2-8 deletion reprogrammed FA metabolism-induced chemoresistance in epithelial ovarian cancer (EOC).

Methods: The deletion frequency and expression of NKX2-8 in 144 EOC specimens were assayed using Fluorescence in situ hybridization and immunochemical assays. The effects of NKX2-8 deletion and the fatty acid oxidation (FAO) antagonist Perhexiline on chemoresistance were examined by Annexin V and colony formation in vitro, and via an intraperitoneal tumor model in vivo. The mechanisms of NKX2-8 deletion in reprogrammed FA metabolism was determined using Chip-seq, metabolomic analysis, FAO assays and immunoprecipitation assays.

Findings: NKX2-8 deletion was correlated with the overall and relapse-free survival of EOC patients. NKX2-8 inhibited the FAO pathway by epigenetically suppressing multiple key components of the FAO cascade, including CPT1A and CPT2. Loss of NKX2-8 resulted in reprogramming of FA metabolism of EOC cells in an adipose microenvironment and leading to platinum resistance. Importantly, pharmacological inhibition of FAO pathway using Perhexiline significantly counteracted NKX2-8 deletion-induced chemoresistance and enhanced platinum's therapeutic efficacy in EOC.

Interpretation: Our results demonstrate that NKX2-8 deletion-reprogrammed FA metabolism contributes to chemoresistance and Perhexiline might serve as a potential tailored treatment for patients with NKX2-8-deleted EOC. FUND: This work was supported by Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities.

Keywords: Chemoresistance; Epithelial ovarian cancer; Fatty acid oxidation; Metabolic reprogram; NKX2–8.

MeSH terms

  • Animals
  • Biomarkers
  • Carcinoma, Ovarian Epithelial / genetics*
  • Carcinoma, Ovarian Epithelial / metabolism*
  • Carcinoma, Ovarian Epithelial / mortality
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics*
  • Fatty Acids / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins / genetics*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Mice
  • Models, Biological
  • Oxidation-Reduction
  • Prognosis
  • Protein Binding
  • Reactive Oxygen Species / metabolism
  • Sequence Deletion*
  • Signal Transduction
  • Transcription Factors / genetics*
  • Tumor Microenvironment

Substances

  • Biomarkers
  • Fatty Acids
  • Homeodomain Proteins
  • NKX2-8 protein, human
  • Reactive Oxygen Species
  • Transcription Factors