Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.
Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.
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肿瘤来源的乳酸通过组蛋白 H3 赖氨酸 18 乳酰化 (H3K18la) 在结直肠癌中促进自噬增强蛋白 RUBCNL 的表达，从而促进对贝伐单抗治疗的耐药性。
DOI：
10.1080/15548627.2023.2249762
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发表时间：
2024-01
期刊：
影响因子：
13.3
通讯作者：
Lin, Junzhong
中科院分区：
文献类型：
--
作者：
Li, Weihao;Zhou, Chi;Yu, Long;Hou, Zhenlin;Liu, Huashan;Kong, Lingheng;Xu, Yanbo;He, Jiahua;Lan, Jin;Ou, Qingjian;Fang, Yujing;Lu, Zhenhai;Wu, Xiaojun;Pan, Zhizhong;Peng, Jianhong;Lin, Junzhong
贝伐单抗在转移性结直肠癌（CRC）的一线和二线治疗中发挥着重要作用。而缺氧的诱导及其对肿瘤的反应在抗血管生成治疗的疗效中起着重要作用，但两者之间的联系尚不清楚。在这里，我们发现乳酸在结直肠癌的肿瘤环境中积累，并作为组蛋白乳酸化的底物，这一过程在缺氧条件下被细胞增强的糖酵解进一步诱导。我们确定，对贝伐单抗治疗有耐药性的结直肠癌患者表现为组蛋白乳酸化水平升高，组蛋白乳酸化抑制有效地抑制了缺氧条件下结直肠癌的肿瘤发生、进展和生存。组蛋白乳酸化促进RUBCNL/Pacer的转录，通过与BECN1 （beclin 1）相互作用促进自噬体成熟，介导III类磷脂酰肌醇3-激酶复合物的募集和功能，在缺氧癌细胞的增殖和存活中起着至关重要的作用。此外，在贝伐单抗耐药患者衍生的临床前模型中，联合抑制组蛋白乳酸化和巨噬/自噬与贝伐单抗治疗显示出显著的治疗效果。这些发现对代谢重编程-表观遗传调控进行了新的探索和重要补充，并为通过抑制组蛋白乳酸化提高贝伐单抗治疗结直肠癌的临床疗效提供了新的策略。缩写：2-DG: 2-脱氧-d -葡萄糖；BECN1: beclin 1；CQ:氯喹;CRC：结直肠癌；DMOG: dimethyloxalylglycine;H3K18la：组蛋白H3赖氨酸18乳酸化；MAP1LC3B/LC3B：微管相关蛋白1轻链3 β；纳拉：乳酸钠；PDO：患者源性器官；PDX：患者来源的异种移植物；RUBCNL/Pacer: rubicon样自噬增强剂；SQSTM1/p62: sequestosome
Bevacizumab plays an important role in the first and second line treatment for metastatic colorectal cancer (CRC). And induction of hypoxia and the tumors response to it plays an important role in determining the efficacy of antiangiogenic therapy while the connection between them remains unclear. Here, we found that lactate accumulated in the tumor environment of CRC and acted as substrates for histone lactylation, and this process was further induced by cellular enhanced glycolysis in hypoxia. We determined that CRC patients resistant to bevacizumab treatment presented with elevated levels of histone lactylation and inhibition of histone lactylation efficiently suppressed CRC tumorigenesis, progression and survival in hypoxia. Histone lactylation promoted the transcription of RUBCNL/Pacer, facilitating autophagosome maturation through interacting with BECN1 (beclin 1) and mediating the recruitment and function of the class III phosphatidylinositol 3-kinase complex, which had a crucial role in hypoxic cancer cells proliferation and survival. Moreover, combining inhibition of histone lactylation and macroautophagy/autophagy with bevacizumab treatment demonstrated remarkable treatment efficacy in bevacizumab-resistance patients-derived pre-clinical models. These findings delivered a new exploration and important supplement of metabolic reprogramming-epigenetic regulation, and provided a new strategy for improving clinical efficacy of bevacizumab in CRC by inhibition of histone lactylation. Abbreviations: 2-DG: 2-deoxy-D-glucose; BECN1: beclin 1; CQ: chloroquine; CRC: colorectal cancer; DMOG: dimethyloxalylglycine; H3K18la: histone H3 lysine 18 lactylation; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Nala: sodium lactate; PDO: patient-derived orgnoid; PDX: patient-derived xenograft; RUBCNL/Pacer: rubicon like autophagy enhancer; SQSTM1/p62: sequestosome 1.
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影响因子：
11.2
作者：
Hu YL;DeLay M;Jahangiri A;Molinaro AM;Rose SD;Carbonell WS;Aghi MK
通讯作者：
Aghi MK
影响因子：
3.8
作者：
Rahbari NN;Reissfelder C;Schulze-Bergkamen H;Jäger D;Büchler MW;Weitz J;Koch M
通讯作者：
Koch M
影响因子：
3.4
作者：
Hurwitz, Herbert
通讯作者：
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影响因子：
3.7
作者：
Maeda, Yoshiaki;Shinohara, Toshiki;Hamada, Tomonori
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抑制自噬增强贝伐珠单抗对肝癌的抗癌作用
影响因子：
4.7
作者：
Guo, Xian-ling;Li, Ding;Wei, Li-xin
通讯作者：
Wei, Li-xin