2. Academic Validation
  3. FOXA3 regulates cholesterol metabolism to compensate for low uptake during the progression of lung adenocarcinoma

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

  • PLoS Biol. 2024 May 28;22(5):e3002621. doi: 10.1371/journal.pbio.3002621.
Dongmei Wang 1 2,  Yuxiang Cao 1,  Meiyao Meng 1,  Jin Qiu 1,  Chao Ni 3,  Xiaozhen Guo 4,  Yu Li 1,  Shuang Liu 1,  Jian Yu 1 5,  Mingwei Guo 1,  Jiawen Wang 1 4,  Bing Du 1,  Wenwei Qiu 6,  Cen Xie 4,  Bing Zhao 3 7,  Xinran Ma 1 5 8,  Xinghua Cheng 9,  Lingyan Xu 1
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
  • 2 Department of Gastrointestinal Surgery, the Affiliated Changzhou, No. 2 People's Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, China.
  • 3 Institute of Organoid Technology, BioGenous Biotechnology, Inc., Suzhou, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 5 Joint Center for Translational Medicine, Fengxian District Central Hospital, Fengxian District, Shanghai, China.
  • 6 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
  • 7 School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
  • 8 Chongqing Key Laboratory of Precision Optics, Chongqing Institute of East China Normal University, Chongqing, China.
  • 9 Department of Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China.
PMID: 38805565 DOI: 10.1371/journal.pbio.3002621
Abstract

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.

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