YY2-CYP51A1 signaling suppresses hepatocellular carcinoma progression by restraining de novo cholesterol biosynthesis

Lingxian Wang; Wei Duan; Cao Ruan; Jingyi Liu; Makoto Miyagishi; Vivi Kasim; Shourong Wu

doi:10.1016/j.bbadis.2025.167658

YY2-CYP51A1 signaling suppresses hepatocellular carcinoma progression by restraining de novo cholesterol biosynthesis

Biochim Biophys Acta Mol Basis Dis. 2025 Jan 4:167658. doi: 10.1016/j.bbadis.2025.167658. Online ahead of print.

Authors

Lingxian Wang¹, Wei Duan¹, Cao Ruan¹, Jingyi Liu¹, Makoto Miyagishi², Vivi Kasim³, Shourong Wu⁴

Affiliations

¹ 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.
² Life Science Innovation, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki 305-0006, Japan.
³ 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; Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing 400030, China. Electronic address: vivikasim@cqu.edu.cn.
⁴ 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; Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing 400030, China. Electronic address: shourongwu@cqu.edu.cn.

PMID: 39761760
DOI: 10.1016/j.bbadis.2025.167658

Abstract

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.

Keywords: CYP51A1; Lipid metabolic reprogramming; Metabolic reprogramming; YY2; de novo cholesterol biosynthesis.