A Proof-of-Concept Inhibitor of Endothelial Lipase Suppresses Triple-Negative Breast Cancer Cells by Hijacking the Mitochondrial Function

Abstract

Triple-negative breast cancer (TNBC) cells reprogram their metabolism to provide metabolic flexibility for tumor cell growth and survival in the tumor microenvironment. While our previous findings indicated that endothelial lipase (EL/LIPG) is a hallmark of TNBC, the precise mechanism through which LIPG instigates TNBC metabolism remains undefined. Here, we report that the expression of LIPG is associated with long non-coding RNA DANCR and positively correlates with gene signatures of mitochondrial metabolism-oxidative phosphorylation (OXPHOS). DANCR binds to LIPG, enabling tumor cells to maintain LIPG protein stability and OXPHOS. As one mechanism of LIPG in the regulation of tumor cell oxidative metabolism, LIPG mediates histone deacetylase 6 (HDAC6) and histone acetylation, which contribute to changes in IL-6 and fatty acid synthesis gene expression. Finally, aided by a relaxed docking approach, we discovered a new LIPG inhibitor, cynaroside, that effectively suppressed the enzyme activity and DANCR in TNBC cells. Treatment with cynaroside inhibited the OXPHOS phenotype of TNBC cells, which severely impaired tumor formation. Taken together, our study provides mechanistic insights into the LIPG modulation of mitochondrial metabolism in TNBC and a proof-of-concept that targeting LIPG is a promising new therapeutic strategy for the treatment of TNBC.

New evidence for a role of DANCR in cancers: a comprehensive review

“…Additionally, DANCR has been shown to interact with proteins and mRNAs. For example, DANCR regulates endothelial lipase (EL/LIPG), a pivotal modulator of tumour cell metabolism, by binding to LIPG and modulating the stable expression of the LIPG protein in TNBC cells [27]. Moreover, studies have indicated that DANCR enhances the stability of the PSMD10 mRNA by interacting with the PSMD10 3'-UTR to counteract the inhibitory effects imposed by miRNAs such as miR-214 and miR-1254 [28].…”

“…Moreover, DANCR interacts with RXRA, promoting its phosphorylation and activating the PI3K/AKT signalling pathway, promoting TNBC progression [47]. Yang et al [27] [5]. In addition, miR-29b-1/a [54], lidocaine and bupivacaine [30] were shown to downregulate DANCR expression, inhibiting cancer cell progression.…”