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- Title
FOXA3 regulates cholesterol metabolism to compensate for low uptake during the progression of lung adenocarcinoma.
- Authors
Wang, Dongmei; Cao, Yuxiang; Meng, Meiyao; Qiu, Jin; Ni, Chao; Guo, Xiaozhen; Li, Yu; Liu, Shuang; Yu, Jian; Guo, Mingwei; Wang, Jiawen; Du, Bing; Qiu, Wenwei; Xie, Cen; Zhao, Bing; Ma, Xinran; Cheng, Xinghua; Xu, Lingyan
- 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. 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.
- Subjects
TRANSCRIPTION factors; LUNGS; LIPID metabolism; ADENOCARCINOMA; CANCER invasiveness; HYDROXYCHOLESTEROLS; CHOLESTEROL metabolism
- Publication
PLoS Biology, 2024, Vol 22, Issue 5, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3002621