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Targeting ONECUT3 blocks glycolytic metabolism and potentiates anti-PD-1 therapy in pancreatic cancer

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Abstract

Background

Reprogramming glucose metabolism, also known as the Warburg effect (aerobic glycolysis), is a hallmark of cancers. Increased tumor glycolysis not only favors rapid cancer cell proliferation but reprograms the immune microenvironment to enable tumor progression. The transcriptional factor ONECUT3 plays key roles in the development of the liver and pancreas, however, limited is known about its oncogenic roles, particularly metabolic reprogramming.

Methods

Immunohistochemistry and Western blotting are applied to determine the expression pattern of ONECUT3 and its clinical relevance in pancreatic ductal adenocarcinoma (PDAC). Knockdown and overexpression strategies are employed to determine the in vitro and in vivo functions of ONECUT3. Chromatin immunoprecipitation, luciferase reporter assay, and gene set enrichment analysis are used to decipher the molecular mechanisms.

Results

The glycolytic metabolism is inversely associated with T-cell infiltration in PDAC. ONECUT3 is identified as a key regulator for PDAC glycolysis and CD8+ T-cell infiltration. Genetic silencing of ONECUT3 inhibits cell proliferation, promotes cell apoptosis, and reduces glycolytic metabolism as evidenced by glucose uptake, lactate production, and extracellular acidification rate. Opposite effects of ONECUT3 are observed in overexpression studies. ONECUT3 enhances aerobic glycolysis via transcriptional regulation of PDK1. Targeting ONECUT3 effectively suppresses tumor growth, increases CD8+ T-cell infiltration, and potentiates anti-PD-1 therapy in PDAC. Pharmacological inhibition of PDK1 also shows a synergistic effect with anti-PD-1 therapy. In clinical setting, ONECUT3 is closely associated with PDK1 expression and T-cell infiltration in PDAC and acts as an independent prognostic factor.

Conclusions

Our study reveals a previous unprecedented regulatory role of ONECUT3 in PDAC glycolysis and provides in vivo evidence that increased glycolysis is linked to an immunosuppressive microenvironment. Moreover, targeting ONECUT3-PDK1 axis may serve as a promising therapeutic approach for the treatment of PDAC.

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Data Availability

The data generated or analyzed during this study are included in this article.

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Acknowledgements

This research was funded by the Jiading District Medical Key Discipline Foundation of Shanghai, China, grant number 2020-jdyxzdxk-06.

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Author notes

  1. Peng-Cheng Chen and Yong Ning contributed equally to this work.

Authors and Affiliations

  1. Department of General Surgery, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, 201800, P.R. China

    Peng-Cheng Chen, Yong Ning, Jin-Gen Su, Jiang-Bo Shen, Qing-Chun Feng, Pei-Dong Shi & Run-Sheng Guo

  2. State Key Laboratory of Oncogenes and Related Genes, Ren Ji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, 200240, P.R. China

    Hui Li & Shu-Heng Jiang

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  1. Peng-Cheng Chen
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Contributions

Peng-Cheng Chen, Yong Ning, Shu-Heng Jiang and Jin-Gen Su performed the experiments. Hui Li contributed bioinformatic analysis. Pei-Dong Shi, Run-Sheng Guo, Shu-Heng Jiang and Jiang-Bo Shen contributed to the conception and design of these studies. Peng-Cheng Chen and Qin-Chun Feng analyzed the data. All authors reviewed the manuscript.

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Correspondence to Pei-Dong Shi or Run-Sheng Guo.

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Chen, PC., Ning, Y., Li, H. et al. Targeting ONECUT3 blocks glycolytic metabolism and potentiates anti-PD-1 therapy in pancreatic cancer. Cell Oncol. 47, 81–96 (2024). https://doi.org/10.1007/s13402-023-00852-3

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