LIPG signaling promotes tumor initiation and metastasis of human basal-like triple-negative breast cancer.
LIPG signaling promotes tumor initiation and metastasis of human basal-like triple-negative breast cancer.
复制标题
作者：
Lo PK;Yao Y;Lee JS;Zhang Y;Huang W;Kane MA;Zhou Q
目前对侵袭性人类基底细胞样三阴性乳腺癌（TNBC）的了解仍然不完整。在这项研究中，我们发现内皮脂肪酶（LIPG）在基底样TNBC中异常过表达。我们证明了LIPG是TNBC细胞体内致瘤性和转移所必需的。LIPG具有支持癌细胞增殖的脂肪酶依赖性功能和促进TNBC的侵袭性、干性和基底/上皮-间充质转化特征的脂肪酶非依赖性功能。从机制上讲，LIPG通过参与干扰素相关的DTX 3L-ISG 15信号传导来执行其致癌功能，DTX 3L-ISG 15信号传导通过ISGylation调节蛋白质功能和稳定性。我们表明，DTX 3L，E3-泛素连接酶，是通过抑制蛋白酶体介导的LIPG降解来维持TNBC细胞中LIPG蛋白水平所必需的。LIPG的失活损害了DTX 3L-ISG 15信号传导，表明存在DTX 3L-LIPG-ISG 15信号传导。我们进一步揭示了LIPG-ISG 15信号转导是不依赖于脂肪酶的。我们证明了DTX 3L-LIPG-ISG 15信号传导对于TNBC细胞的恶性肿瘤是必需的。靶向该途径为基底样TNBC治疗提供了新的策略。
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.