Wang Lingxian, Duan Wei, Ruan Cao, Liu Jingyi, Miyagishi Makoto, Kasim Vivi, Wu Shourong
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China; The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China.
Life Science Innovation, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki 305-0006, Japan.
Biochim Biophys Acta Mol Basis Dis. 2025 Mar;1871(3):167658. doi: 10.1016/j.bbadis.2025.167658. Epub 2025 Jan 4.
Lipid accumulation is a frequently observed characteristic of cancer. Lipid accumulation is closely related to tumor progression, metastasis, and drug resistance; however, the mechanism underlying lipid metabolic reprogramming in tumor cells is not fully understood. Yin yang 2 (YY2) is a C2H2‑zinc finger transcription factor that exerts tumor-suppressive effects. However, its involvement in tumor cell lipid metabolic reprogramming remains unclear. In the present study, we identified YY2 as a novel regulator of cholesterol metabolism. We showed that YY2 suppressed cholesterol accumulation in hepatocellular carcinoma (HCC) cells by downregulating the transcriptional activity of cytochrome P450 family 51 subfamily A member 1 (CYP51A1), a key enzyme in de novo cholesterol biosynthesis. Subsequently, through in vitro and in vivo experiments, we demonstrated that this downregulation is crucial for the YY2 tumor suppressive effect. Together, our findings unraveled a previously unprecedented regulation of HCC cells cholesterol metabolism, and eventually, their tumorigenic potential, through YY2 negative regulation on CYP51A1 expression. This study revealed a novel regulatory mechanism of lipid metabolic reprogramming in tumor cells and provided insights into the molecular mechanism underlying the YY2 the suppressive effect. Furthermore, our findings suggest a potential antitumor therapeutic strategy targeting cholesterol metabolic reprogramming using YY2.
脂质蓄积是癌症常见的特征。脂质蓄积与肿瘤进展、转移及耐药性密切相关；然而，肿瘤细胞中脂质代谢重编程的潜在机制尚未完全明确。阴阳2（YY2）是一种发挥肿瘤抑制作用的C2H2型锌指转录因子。然而，其在肿瘤细胞脂质代谢重编程中的作用仍不清楚。在本研究中，我们鉴定出YY2是胆固醇代谢的新型调节因子。我们发现YY2通过下调细胞色素P450家族51亚家族A成员1（CYP51A1）的转录活性来抑制肝癌（HCC）细胞中的胆固醇蓄积，CYP51A1是从头合成胆固醇的关键酶。随后，通过体外和体内实验，我们证明这种下调对于YY2的肿瘤抑制作用至关重要。总之，我们的研究结果揭示了通过YY2对CYP51A1表达的负调控，对HCC细胞胆固醇代谢及其致瘤潜能进行了前所未有的调控。本研究揭示了肿瘤细胞脂质代谢重编程的新调控机制，并为YY2抑制作用的分子机制提供了见解。此外，我们的研究结果提示了一种利用YY2靶向胆固醇代谢重编程的潜在抗肿瘤治疗策略。
