2. Academic Validation
  3. 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

  • Autophagy. 2023 Aug 29;1-17. doi: 10.1080/15548627.2023.2249762.
Weihao Li 1 2,  Chi Zhou 1 2,  Long Yu 1 2,  Zhenlin Hou 1 2,  Huashan Liu 3,  Lingheng Kong 1 2,  Yanbo Xu 1 2,  Jiahua He 1 2,  Jin Lan 1 2,  Qingjian Ou 1 2,  Yujing Fang 1 2,  Zhenhai Lu 1 2,  Xiaojun Wu 1 2,  Zhizhong Pan 1 2,  Jianhong Peng 1 2,  Junzhong Lin 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
  • 2 Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
  • 3 Department of Colorectal Surgery and Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
PMID: 37615625 DOI: 10.1080/15548627.2023.2249762
Abstract

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.

Keywords

Antiangiogenesis; autophagy; colorectal cancer; histone lactylation; hypoxia.

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