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

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. <b>Abbreviations:</b> 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.

贝伐珠单抗（Bevacizumab）在转移性结直肠癌（colorectal cancer, CRC）的一线与二线治疗中具有重要地位。缺氧诱导以及肿瘤对缺氧的应答，对抗血管生成治疗的疗效至关重要，但二者之间的关联仍未明确。本研究发现，结直肠癌肿瘤微环境中存在乳酸蓄积现象，乳酸可作为组蛋白乳酸化的底物，且该过程可被缺氧条件下增强的细胞糖酵解进一步促进。我们证实，对贝伐珠单抗耐药的结直肠癌患者，其组蛋白乳酸化水平升高；而抑制组蛋白乳酸化，可有效抑制缺氧条件下结直肠癌的发生、进展以及癌细胞存活。组蛋白乳酸化可促进RUBCNL/Pacer的转录，通过与BECN1（Beclin 1）相互作用，并介导III类磷脂酰肌醇3-激酶复合物的招募与功能，从而促进自噬体成熟，该过程在缺氧癌细胞的增殖与存活中发挥关键作用。此外，在贝伐珠单抗耐药患者来源的临床前模型中，联合抑制组蛋白乳酸化与巨自噬/自噬并联用贝伐珠单抗治疗，展现出显著的治疗效果。本研究为代谢重编程-表观遗传调控领域提供了新的探索方向与重要补充，并为通过抑制组蛋白乳酸化提升贝伐珠单抗在结直肠癌治疗中的临床疗效提供了全新策略。
<b>缩写说明:</b> 2-DG：2-脱氧-D-葡萄糖（2-deoxy-D-glucose）；BECN1：Beclin 1；CQ：氯喹（chloroquine）；CRC：结直肠癌（colorectal cancer）；DMOG：二甲基乙二酰基甘氨酸（dimethyloxalylglycine）；H3K18la：组蛋白H3赖氨酸18乳酸化（histone H3 lysine 18 lactylation）；MAP1LC3B/LC3B：微管相关蛋白1轻链3β（microtubule associated protein 1 light chain 3 beta）；Nala：乳酸钠（sodium lactate）；PDO：患者来源类器官（patient-derived organoid，原文拼写为orgnoid，疑似笔误）；PDX：患者来源异种移植瘤（patient-derived xenograft）；RUBCNL/Pacer：类Rubicon自噬增强因子（rubicon like autophagy enhancer）；SQSTM1/p62：自噬衔接蛋白p62（sequestosome 1）