Zhang Xia, Qiu Li, Zhang Lei, Li Wenfang, Xiang Debing, Wang Jian, Wu Shourong, Kasim Vivi
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing University, Chongqing 400044, China.
The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China.
Int J Mol Sci. 2025 May 29;26(11):5210. doi: 10.3390/ijms26115210.
Tumor cells alter lipid metabolic pathways to meet their demands for energy and membrane biosynthesis. Despite its crucial role in tumor cell growth, survival, and metastasis, the mechanisms underlying tumor cell lipid metabolic reprogramming remain poorly understood. Pre-B-cell leukemia transcription factor 3 (PBX3), a member of the PBX family, could promote tumorigenesis; however, whether it is involved in tumor lipid metabolic reprogramming remains unknown. Herein, we found that PBX3 significantly promotes tumor growth by enhancing lipid accumulation in HCC cells. By assessing the effect of PBX3 on the expression levels of lipid metabolism-related genes, we found that PBX3 could positively regulate the expression of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), a rate-limiting enzyme in the cholesterol biosynthesis pathway. Mechanistically, we revealed that PBX3 could directly bind to the -167/-151 region of promoter, thereby increasing its transcriptional activity and, subsequently, its expression level. This leads to the increase of HCC cell cholesterol biosynthesis and, eventually, to the increase of the in vivo tumorigenic potential. Collectively, our research revealed an unprecedented regulatory mechanism of cholesterol metabolism in HCC cells through PBX3 positive regulation on HMGCR expression levels. These findings provide novel insights into tumor metabolic reprogramming and uncover a previously unknown physiological function for PBX3. Moreover, these results suggest the potential of targeting as an anti-tumor therapeutic strategy.
肿瘤细胞改变脂质代谢途径以满足其对能量和膜生物合成的需求。尽管其在肿瘤细胞生长、存活和转移中起关键作用，但肿瘤细胞脂质代谢重编程的潜在机制仍知之甚少。前B细胞白血病转录因子3（PBX3）是PBX家族的成员之一，可促进肿瘤发生；然而，它是否参与肿瘤脂质代谢重编程尚不清楚。在此，我们发现PBX3通过增强肝癌细胞中的脂质积累显著促进肿瘤生长。通过评估PBX3对脂质代谢相关基因表达水平的影响，我们发现PBX3可以正向调节3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）的表达，HMGCR是胆固醇生物合成途径中的限速酶。机制上，我们揭示PBX3可以直接结合到启动子的-167/-151区域，从而增加其转录活性，进而增加其表达水平。这导致肝癌细胞胆固醇生物合成增加，并最终导致体内肿瘤发生潜能增加。总的来说，我们的研究揭示了肝癌细胞中通过PBX3对HMGCR表达水平的正向调节而产生的前所未有的胆固醇代谢调节机制。这些发现为肿瘤代谢重编程提供了新的见解，并揭示了PBX3以前未知的生理功能。此外，这些结果表明靶向治疗作为一种抗肿瘤治疗策略的潜力。
