IL-33-Induced Transcriptional Activation of LPIN1 Accelerates Breast Tumorigenesis

SIMPLE SUMMARY: LPIN1 is a protein that exhibits dual functions as a phosphatidic acid phosphatase enzyme in the regulation of triglyceride and glycerophospholipid metabolism and a transcriptional coregulator. Recent advances in understanding suggest that LPIN1 frequently observed in various human cancer cell lines controls the main cellular processes in cancer progression. Therefore, there is considerable interest in the underlying mechanism regulating LPIN1 expression. We have determined for the first time that IL-33 regulates LPIN1 expression by recruiting c-Jun to the LPIN1 promoter. Consistent with these observations, IL-33 levels positively correlate with LPIN1 expression in human breast cancer. Our findings point to a critical role of IL-33-induced LPIN1 expression via COT/JNK1/2 pathway in promoting epithelial transformation and breast tumorigenesis. ABSTRACT: Phospholipids are crucial materials that are not only required for cell membrane construction but also play significant roles as signaling molecules. LPIN1 is an enzyme that displays phosphatidate phosphatase activity in the triglyceride and phospholipid synthesis pathway. Recent studies have shown that overexpression of LPIN1 is involved in breast tumorigenesis, but the underlying mechanism regulating LPIN1 expression has not been elucidated yet. In the present study, we showed that the IL-33-induced COT-JNK1/2 signaling pathway regulates LPIN1 mRNA and protein expression by recruiting c-Jun to the LPIN1 promoter in breast cancer cells. IL-33 dose-dependently and time-dependently increased LPIN1 mRNA and protein expression. Moreover, IL-33 promoted colony formation and mammary tumorigenesis via induction of LPIN1 expression, while inhibition of LPIN1 disturbed IL-33-induced cell proliferation and mammary tumorigenesis. IL-33-driven LPIN1 expression was mediated by the COT-JNK1/2 signaling pathway, and inhibition of COT or JNK1/2 reduced LPIN1 expression. COT-JNK1/2-mediated IL-33 signaling activated c-Jun and promoted its binding to the promoter region of LPIN1 to induce LPIN1 expression. These findings demonstrated the regulatory mechanism of LPIN1 transcription by the IL-33-induced COT/JNK1/2 pathway for the first time, providing a potential mechanism underlying the upregulation of LPIN1 in cancer.