LPCAT1 reprogramming cholesterol metabolism promotes the progression of esophageal squamous cell carcinoma

• Published in: Cell death & disease 2021-09, Vol.12 (9), p.845-14, Article 845
• Main Authors: Tao, Mingyue, Luo, Jing, Gu, Tong, Yu, Xiaojuan, Song, Zhen, Jun, Yali, Gu, Hao, Han, Kairong, Huang, Xiujuan, Yu, Weiyong, Sun, Su’an, Zhang, Zhengwei, Liu, Lu, Chen, Xiaofei, Zhang, Li, Luo, Chao, Wang, Qilong
• Format: Article
• Language: English
• Subjects: 1-Acylglycerophosphocholine O-acyltransferase; 1-Acylglycerophosphocholine O-Acyltransferase - genetics; 1-Acylglycerophosphocholine O-Acyltransferase - metabolism; 1-Phosphatidylinositol 3-kinase; 38; 38/109; 631/67/2327; 692/699/67/2195; 82/1; 82/51; 96/31; 96/95; Acyltransferase; Animals; Anoikis - genetics; Antibodies; Apoptosis - genetics; Base Sequence; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Cycle - genetics; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Cell proliferation; Cell Proliferation - genetics; Cholesterol; Cholesterol - metabolism; Disease Progression; Esophageal cancer; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma - metabolism; Esophageal Squamous Cell Carcinoma - pathology; Esophagus; Female; Gene Expression Regulation, Neoplastic; Humans; Immunology; Life Sciences; Lipid metabolism; Low density lipoprotein; Lysophosphatidylcholine; Male; Metabolism; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Neoplasm Invasiveness; Neoplasm Proteins - metabolism; Patients; Prognosis; Signal Transduction; Squamous cell carcinoma; Sterol regulatory element-binding protein; Transcription Factors - metabolism; Transcription, Genetic; Tumor cells; Tumors; Up-Regulation - genetics; Xenografts
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04132-6

Tumor cells require high levels of cholesterol for membrane biogenesis for rapid proliferation during development. Beyond the acquired cholesterol from low-density lipoprotein (LDL) taken up from circulation, tumor cells can also biosynthesize cholesterol. The molecular mechanism underlying cholesterol anabolism in esophageal squamous cell carcinoma (ESCC) and its effect on patient prognosis are unclear. Dysregulation of lipid metabolism is common in cancer. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has been implicated in various cancer types; however, its role in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we identified that LPCAT1 is highly expressed in ESCC and that LPCAT1 reprograms cholesterol metabolism in ESCC. LPCAT1 expression was negatively correlated with patient prognosis. Cholesterol synthesis in ESCC cells was significantly inhibited following LPCAT1 knockdown; cell proliferation, invasion, and migration were significantly reduced, along with the growth of xenograft subcutaneous tumors. LPCAT1 could regulate the expression of the cholesterol synthesis enzyme, SQLE, by promoting the activation of PI3K, thereby regulating the entry of SP1/SREBPF2 into the nucleus. LPCAT1 also activates EGFR leading to the downregulation of INSIG-1 expression, facilitating the entry of SREBP-1 into the nucleus to promote cholesterol synthesis. Taken together, LPCAT1 reprograms tumor cell cholesterol metabolism in ESCC and can be used as a potential treatment target against ESCC.