Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jan;20(1):114-130.
doi: 10.1080/15548627.2023.2249762. Epub 2023 Aug 29.

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

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

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

Weihao Li et al. Autophagy. 2024 Jan.

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.

PubMed Disclaimer

Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Colorectal cancer (CRC) resistance to bevacizumab treatment exhibited increased lactylation levels which was associated with poor survival in CRC patients.
Figure 2.
Figure 2.
Effects of histone lactylation inhibition on colorectal cancer cells proliferation and survival in hypoxia.
Figure 3.
Figure 3.
Histone lactylation activated RUBCNL transcription in colorectal cancer.
Figure 4.
Figure 4.
Histone lactylation promoted colorectal cancer cells survival and proliferation in hypoxia through RUBCNL.
Figure 5.
Figure 5.
RUBCNL promoted autophagasome maturation through mediating the recruitment and function of PtdIns3K complex.
Figure 6.
Figure 6.
Histone lactylation inhibition enhanced antitumor effects of bevacizumab in colorectal cancer.
Figure 7.
Figure 7.
In colorectal cancer cells, high histone lactylation level induced by aerobic glycolysis promotes the transcription of RUBCNL, which enhances autophagy through promoting autophagasome maturation, and contributes to colorectal cancer tumorigenesis and progression. When receiving bevacizumab, the glycolysis of cancer cell in hypoxic regions may be further enhanced, followed by higher levels of histone lactylation and RUBCNL is transcriptionally upregulated by histone lactylation, which contributes to colorectal cancer cells survival and therapy resistance.
See this image and copyright information in PMC

References

    1. Sung H, Ferlay J, Siegel RL, et al. Global cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. doi: 10.3322/caac.21660 - DOI - PubMed
    1. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA A Cancer J Clin. 2020;70(3):145–164. doi: 10.3322/caac.21601 - DOI - PubMed
    1. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386–1422. doi: 10.1093/annonc/mdw235 - DOI - PubMed
    1. Jönsson K, Gröndahl G, Salö M, et al. Repeated liver resection for colorectal liver metastases: a comparison with primary liver resections concerning perioperative and long-term outcome. Gastroenterol Res Pract. 2012;2012:568214. doi: 10.1155/2012/568214 - DOI - PMC - PubMed
    1. Rahbari NN, Reissfelder C, Schulze-Bergkamen H, et al. Adjuvant therapy after resection of colorectal liver metastases: the predictive value of the MSKCC clinical risk score in the era of modern chemotherapy. BMC Cancer. 2014;14(1):174. doi: 10.1186/1471-2407-14-174 - DOI - PMC - PubMed

Publication types