LIPG signaling promotes tumor initiation and metastasis of human basal-like triple-negative breast cancer
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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/31334 |
| _version_ | 1811235889163010048 |
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| author | Pang-Kuo Lo Yuan Yao Ji Shin Lee Yongshu Zhang Weiliang Huang Maureen A Kane Qun Zhou |
| author_facet | Pang-Kuo Lo Yuan Yao Ji Shin Lee Yongshu Zhang Weiliang Huang Maureen A Kane Qun Zhou |
| author_sort | Pang-Kuo Lo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:00:09Z |
| format | Article |
| id | doaj.art-409abe3563fc4e4f877e70ee3b731b2a |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:00:09Z |
| publishDate | 2018-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-409abe3563fc4e4f877e70ee3b731b2a2022-12-22T03:33:53ZengeLife Sciences Publications LtdeLife2050-084X2018-01-01710.7554/eLife.31334LIPG signaling promotes tumor initiation and metastasis of human basal-like triple-negative breast cancerPang-Kuo Lo0https://orcid.org/0000-0001-7202-3162Yuan Yao1Ji Shin Lee2Yongshu Zhang3Weiliang Huang4Maureen A Kane5Qun Zhou6https://orcid.org/0000-0003-1745-0369Department of Biochemistry and Molecular Biology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, United StatesDepartment of Biochemistry and Molecular Biology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, United StatesDepartment of Pathology, Chonnam National University Medical School, Gwangju, KoreaDepartment of Biochemistry and Molecular Biology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, United StatesDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, United StatesDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, United StatesDepartment of Biochemistry and Molecular Biology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, United StatesCurrent 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.https://elifesciences.org/articles/31334Basal-like TNBCendothelial lipaseLIPGDTX3LISG15 |
| spellingShingle | Pang-Kuo Lo Yuan Yao Ji Shin Lee Yongshu Zhang Weiliang Huang Maureen A Kane Qun Zhou LIPG signaling promotes tumor initiation and metastasis of human basal-like triple-negative breast cancer eLife Basal-like TNBC endothelial lipase LIPG DTX3L ISG15 |
| title | LIPG signaling promotes tumor initiation and metastasis of human basal-like triple-negative breast cancer |
| title_full | LIPG signaling promotes tumor initiation and metastasis of human basal-like triple-negative breast cancer |
| title_fullStr | LIPG signaling promotes tumor initiation and metastasis of human basal-like triple-negative breast cancer |
| title_full_unstemmed | LIPG signaling promotes tumor initiation and metastasis of human basal-like triple-negative breast cancer |
| title_short | LIPG signaling promotes tumor initiation and metastasis of human basal-like triple-negative breast cancer |
| title_sort | lipg signaling promotes tumor initiation and metastasis of human basal like triple negative breast cancer |
| topic | Basal-like TNBC endothelial lipase LIPG DTX3L ISG15 |
| url | https://elifesciences.org/articles/31334 |
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