LIPG signaling promotes tumor initiation and metastasis of human basal-like triple-negative breast cancer
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AbstractCurrent understanding of aggressive human basal-like triple-negative breast cancer (TNBC) remains incomplete. In this study, we show endothelial lipase (LIPG) is aberrantly overexpressed in basal-like TNBCs. We demonstrate that LIPG is required for in vivo tumorigenicity and metastasis of TNBC cells. LIPG possesses a lipase-dependent function that supports cancer cell proliferation and a lipase-independent function that promotes invasiveness, stemness and basal/ epithelial-mesenchymal transition features of TNBC. Mechanistically, LIPG executes its oncogenic function through its involvement in interferon-related DTX3L-ISG15 signaling, which regulates protein function and stability by ISGylation. We show that DTX3L, an E3-ubiquitin ligase, is required for maintaining LIPG protein levels in TNBC cells by inhibiting proteasome-mediated LIPG degradation. Inactivation of LIPG impairs DTX3L-ISG15 signaling, indicating the existence of DTX3L-LIPG-ISG15 signaling. We further reveal LIPG-ISG15 signaling is lipase-independent. We demonstrate that DTX3L-LIPG-ISG15 signaling is essential for malignancies of TNBC cells. Targeting this pathway provides a novel strategy for basal-like TNBC therapy. Copyright Lo et al.
SponsorsThis work was supported, in whole or in part, by the NIH CA157779A1 and CA163820A1, and the University of Maryland Baltimore, School of Pharmacy Mass Spectrometry Center (SOP1841-IQB2014).
Triple Negative Breast Neoplasms--physiopathology
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85042118944&doi=10.7554%2feLife.31334&partnerID=40&md5=3898bb5a3f2a9a700f7651cfea08381e; http://hdl.handle.net/10713/9261