华南理工大学孙林冲等研究人员合作发现，ENO1–BACE2介导的LDLR切割通过重塑胆固醇代谢促进肝癌进展。该项研究成果于2025年2月6日在线发表在《分子细胞生物学报》上。

研究人员发现烯醇化酶1（ENO1）可以与β位淀粉样前体蛋白切割酶2（BACE2）结合，BACE2是ENO1的共依赖基因，且这种结合发生在肝癌细胞中。通过抑制溶酶体依赖性降解，ENO1稳定了BACE2蛋白水平，而不影响其mRNA水平。

进一步分析揭示，ENO1和BACE2促进低密度脂蛋白受体（LDLR）的切割，导致外源性胆固醇的吸收减少。为了维持细胞内胆固醇水平，ENO1和BACE2通过负反馈机制上调参与新生胆固醇合成的基因表达。无论是在体外还是体内，BACE2介导了ENO1在肝癌中的促肿瘤作用。

最后，研究人员在临床肝细胞癌（HCC）样本中检测到ENO1和BACE2的高表达以及LDLR的低表达，ENO1–BACE2–LDLR轴的异常表达与肝癌患者的差预后显著相关。

这些数据共同表明，ENO1通过与BACE2结合在蛋白质切割中发挥作用，并通过重新编程胆固醇代谢促进肝癌进展。

据介绍，ENO1是一种参与肿瘤进展的糖酵解酶，执行多种经典和非经典功能。然而，它促进肿瘤进展的机制仍未完全了解。

附：英文原文

Title: ENO1–BACE2-mediated LDLR cleavage promotes liver cancer progression by remodelling cholesterol metabolism

Author: Li, Zhikun, Fan, Kaixiang, Suo, Caixia, Gu, Xuemei, Zhu, Chuxu, Wei, Haoran, Chen, Liang, Gao, Ping, Sun, Linchong

Issue&Volume: 2025-02-06

Abstract: Enolase 1 (ENO1) is a glycolytic enzyme involved in tumour progression that performs a variety of classical and nonclassical functions. However, the mechanism by which it promotes tumour progression is still not fully understood. Here, we found that ENO1 can bind to β-site amyloid precursor protein cleaving enzyme 2 (BACE2), a codependent gene of ENO1, in liver cancer cells. By suppressing lysosomal-dependent degradation, ENO1 stabilises BACE2 protein level without affecting its mRNA level. Further analysis revealed that ENO1 and BACE2 promote low-density lipoprotein receptor (LDLR) cleavage, leading to decreased absorption of exogenous cholesterol. To maintain intracellular cholesterol levels, ENO1 and BACE2 upregulate the expression of genes involved in de novo cholesterol synthesis through a negative feedback mechanism. Both in vitro and in vivo, BACE2 mediates the tumour-promoting effect of ENO1 in liver cancer. Finally, high expression levels of ENO1 and BACE2 and low expression levels of LDLR were detected in clinical HCC samples, and abnormal expression of the ENO1–BACE2–LDLR axis was significantly associated with poor prognosis in patients with liver cancer. These data collectively demonstrated that ENO1 functions in protein cleavage by binding to BACE2 and promotes liver cancer progression by reprogramming cholesterol metabolism.

DOI: 10.1093/jmcb/mjaf001

Source: https://dx.doi.org/10.1093/jmcb/mjaf001