Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
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.
PLoS Biol. 2024 May 28;22(5):e3002621. doi: 10.1371/journal.pbio.3002621. eCollection 2024 May.
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.
胆固醇代谢对多种癌症的进展至关重要，而胆固醇如何影响肺癌这一低胆固醇组织的转移以及潜在机制尚不清楚。在这项研究中，我们发现转移性肺腺癌细胞通过内源性胆固醇生物合成获得细胞脱氢胆固醇和胆固醇，而不是在胆固醇处理时摄取。此外，我们证明了外源性胆固醇作为信号分子通过 GLI2 诱导 FOXA3，这是脂质代谢的关键转录因子。随后，ChIP-seq 分析和分子研究表明，FOXA3 转录激活胆固醇生物合成的必需酶 Hmgcs1，以诱导内源性脱氢胆固醇和胆固醇水平，从而改变膜组成和细胞迁移。相反，FOXA3 的敲低或敲除阻断了胆固醇生物合成和肺腺癌细胞在小鼠中的转移。此外，强效 FOXA3 抑制剂厚朴酚抑制了肺腺癌细胞来源的类器官（PDOs）中的转移基因程序。总之，我们的研究结果揭示了独特的胆固醇代谢和 FOXA3 对肺腺癌转移的贡献。
