NKX2-8 Deletion Confers Chemoresistance via Reprogramming of Fatty Acid Metabolism in Epithelial Ovarian Cancer

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.   Funding Statement: This work was supported by Natural Science Foundation of China (No. 81830082, 91740119, 91529301, 81621004, 91740118, 81773106 and 81530082); Guangzhou Science and Technology Plan Projects (201803010098); Natural Science Foundation of Guangdong Province (2018B030311009 and 2016A030308002); The Fundamental Research Funds for the Central Universities [No. 17ykjc02]. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: Prior donor consent and approval were obtained from the Institutional Research Ethics Committee. All experimental procedures were approved by the Institutional Animal Care and Use Committee of Sun Yat-sen University