Current 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.
- Qun Zhou
- Qun Zhou
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: This animal study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#0116028) of the University of Maryland School of Medicine.
Human subjects: Breast cancer tissue samples from breast cancer patients were provided by the Chonnam National University Hwasun Hospital National Biobank of Korea, a member of the National Biobank of Republic of Korea, which is supported by the Ministry of Health, Welfare and Family Affairs. All tissue samples were obtained with informed consent from patients under protocols approved by the institutional review board of the Chonnam National University Hwasun Hospital. The use of human tissue specimens in this study has been approved by the institutional review board of the Chonnam National University Hwasun Hospital (Reference number: CNUHH-2016-153). The institutional approval is not required for publication of data from these human specimens due to institutional policies of the Chonnam National University Hwasun Hospital.
- Ralph DeBerardinis, UT Southwestern Medical Center, United States
© 2018, Lo et al.
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