#结直肠癌研究进展#【《Nature Metabolism》——结直肠癌（CRC）潜在治疗靶点：糖酵解酶烯醇化酶2（ENO2）】

糖酵解酶烯醇化酶2（ENO2）是结直肠癌（CRC）患者对抗血管生成治疗产生耐药性的驱动因素，是一个潜在的治疗靶点。

【题目】ENO2的代谢产物磷酸烯醇丙酮酸作为HDAC1的内源性抑制剂发挥作用，并导致抗血管生成治疗的耐药性

【摘要】代谢重编程与癌症中抗血管生成治疗的耐药性相关。然而，其分子机制尚未明确。在本研究中，我们发现糖酵解酶烯醇化酶2（ENO2）是结直肠癌（CRC）小鼠模型和人类患者对抗血管生成治疗产生耐药性的驱动因素。ENO2过表达诱导神经内分泌分化，促进结直肠癌恶化，并使结直肠癌对抗血管生成药物不敏感。机制上，ENO2的代谢产物磷酸烯醇丙酮酸（PEP）选择性地抑制组蛋白去乙酰化酶1（HDAC1）的活性，从而增加β-catenin的乙酰化并激活结直肠癌中β-catenin通路。用烯醇酶抑制剂AP-III-a4或POMHEX抑制ENO2可在体外和携带耐药CRC异种移植肿瘤的小鼠中增强抗血管生成药物的疗效。综上，我们的研究结果揭示了ENO2是CRC抗血管生成疗法的耐药性的一个有效的预测生物标志物和治疗靶点，并揭示了PEP作为内源性HDAC1抑制剂在调节抗血管生成治疗耐药中先前未明确的和代谢的独特作用。

英文原文

[Report] The glycolytic enzyme enolase 2 (ENO2) is a driver of resistance to antiangiogenic therapy in patients with colorectal cancer, and is a potential therapeutic targets .

[Title] ENO2-derived phosphoenolpyruvate functions as an endogenous inhibitor of HDAC1 and confers resistance to antiangiogenic therapy
[Authors] Chenran Wang, Maohua Huang, Yuning Lin, Yiming Zhang, Jinghua Pan, Chang Jiang, Minjing Cheng, Shenrong Li, Wenzhuo He, Zhengqiu Li, Zhengchao Tu, Jun Fan, Huhu Zeng, Jiahui Lin, Yongjin Wang, Nan Yao, Tongzheng Liu, Qi Qi, Xiangning Liu, Zhimin Zhang, Minfeng Chen, Liangping Xia, Dongmei Zhang & Wencai Ye

[Abstract] Metabolic reprogramming is associated with resistance to antiangiogenic therapy in cancer. However, its molecular mechanisms have not been clearly elucidated. Here, we identify the glycolytic enzyme enolase 2 (ENO2) as a driver of resistance to antiangiogenic therapy in colorectal cancer (CRC) mouse models and human participants. ENO2 overexpression induces neuroendocrine differentiation, promotes malignant behaviour in CRC and desensitizes CRC to antiangiogenic drugs. Mechanistically, the ENO2-derived metabolite phosphoenolpyruvate (PEP) selectively inhibits histone deacetylase 1 (HDAC1) activity, which increases the acetylation of β-catenin and activates the β-catenin pathway in CRC. Inhibition of ENO2 with enolase inhibitors AP-III-a4 or POMHEX synergizes the efficacy of antiangiogenic drugs in vitro and in mice bearing drug-resistant CRC xenograft tumours. Together, our findings reveal that ENO2 constitutes a useful predictive biomarker and therapeutic target for resistance to antiangiogenic therapy in CRC, and uncover a previously undefined and metabolism-independent role of PEP in regulating resistance to antiangiogenic therapy by functioning as an endogenous HDAC1 inhibitor.

原文链接：

http://t.cn/A6OauFOl