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FOXA3 regulates cholesterol metabolism to compensate for low uptake during the progression of lung adenocarcinoma

文献类型：期刊论文

作者Wang, Dongmei8,9,10; Cao, Yuxiang9,10; Meng, Meiyao9,10; Qiu, Jin9,10; Ni, Chao7; Guo, Xiaozhen6; Li, Yu9,10; Liu, Shuang9,10; Yu, Jian5,9,10; Guo, Mingwei9,10
刊名PLOS BIOLOGY
出版日期2024-05-01
卷号22期号:5页码:29
ISSN号1544-9173
DOI10.1371/journal.pbio.3002621
通讯作者Zhao, Bing(bingzhao@biogenous.cn) ; Ma, Xinran(xrma@bio.ecnu.edu.cn) ; Cheng, Xinghua(chengxinghua_001@163.com) ; Xu, Lingyan(lyxu@bio.ecnu.edu.cn)
英文摘要Cholesterol metabolism is vital for multiple cancer progression, while how cholesterol affects lung, a low-cholesterol tissue, for cancer metastasis and the underlying mechanism remain unclear. In this study, we found that metastatic lung adenocarcinoma cells acquire cellular dehydrocholesterol and cholesterol by endogenous cholesterol biosynthesis, instead of uptake upon cholesterol treatment. Besides, we demonstrated that exogenous cholesterol functions as signaling molecule to induce FOXA3, a key transcription factor for lipid metabolism via GLI2. Subsequently, ChIP-seq analysis and molecular studies revealed that FOXA3 transcriptionally activated Hmgcs1, an essential enzyme of cholesterol biosynthesis, to induce endogenous dehydrocholesterol and cholesterol level for membrane composition change and cell migration. Conversely, FOXA3 knockdown or knockout blocked cholesterol biosynthesis and lung adenocarcinoma metastasis in mice. In addition, the potent FOXA3 inhibitor magnolol suppressed metastatic gene programs in lung adenocarcinoma patient-derived organoids (PDOs). Altogether, our findings shed light onto unique cholesterol metabolism and FOXA3 contribution to lung adenocarcinoma metastasis. Cholesterol is important for cancer progression, yet its levels are low in the lung. How is this overcome during lung cancer? This study shows that exogenous cholesterol can be sensed by lung adenocarcinoma cells, leading to activation of de novo cholesterol biosynthesis through a GLI2-FOXA3-HMGCS1 transcriptional axis, thereby promoting cancer progression.
WOS关键词MEVALONATE PATHWAY ; SERUM-CHOLESTEROL ; CANCER ; DIFFERENTIATION ; ACTIVATION ; EXPRESSION ; STEROLS ; STATINS ; A3
资助项目National Key Research and Development Program of China ; NIDDK, NIH[011] ; ECNU multifunctional platform for Innovation
WOS研究方向Biochemistry & Molecular Biology ; Life Sciences & Biomedicine - Other Topics
语种英语
WOS记录号WOS:001233780300005
出版者PUBLIC LIBRARY SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/311743]  
专题新药研究国家重点实验室
通讯作者Zhao, Bing; Ma, Xinran; Cheng, Xinghua; Xu, Lingyan
作者单位1.Shanghai Jiao Tong Univ, Shanghai Chest Hosp, Shanghai Lung Canc Ctr, Dept Oncol, Shanghai, Peoples R China
2.East China Normal Univ, Chongqing Key Lab Precis Opt, Chongqing Inst, Chongqing, Peoples R China
3.Nanchang Univ, Jiangxi Med Coll, Sch Basic Med Sci, Nanchang, Jiangxi, Peoples R China
4.East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev, Sch Chem & Mol Engn, Shanghai, Peoples R China
5.Fengxian Dist Cent Hosp, Joint Ctr Translat Med, Shanghai, Peoples R China
6.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai, Peoples R China
7.BioGenous Biotechnol Inc, Inst Organoid Technol, Suzhou, Peoples R China
8.Nanjing Med Univ, Affiliated Changzhou Peoples Hosp 2, Changzhou Med Ctr, Dept Gastrointestinal Surg, Changzhou, Jiangsu, Peoples R China
9.East China Normal Univ, Sch Life Sci, Shanghai, Peoples R China
10.East China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Dongmei,Cao, Yuxiang,Meng, Meiyao,et al. FOXA3 regulates cholesterol metabolism to compensate for low uptake during the progression of lung adenocarcinoma[J]. PLOS BIOLOGY,2024,22(5):29.
APA Wang, Dongmei.,Cao, Yuxiang.,Meng, Meiyao.,Qiu, Jin.,Ni, Chao.,...&Xu, Lingyan.(2024).FOXA3 regulates cholesterol metabolism to compensate for low uptake during the progression of lung adenocarcinoma.PLOS BIOLOGY,22(5),29.
MLA Wang, Dongmei,et al."FOXA3 regulates cholesterol metabolism to compensate for low uptake during the progression of lung adenocarcinoma".PLOS BIOLOGY 22.5(2024):29.

入库方式： OAI收割

来源：上海药物研究所

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