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ZMYND8 promotes the Warburg effect and tumorigenesis through c-Myc activation in pancreatic cancer

Oncogene volume 44, pages 3083–3095 (2025)Cite this article

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Abstract

Pancreatic cancer (PC) is a digestive tract tumour with an extremely poor patient prognosis and prominent metabolic abnormalities. However, the molecular mechanisms underlying metabolic reprogramming in the progression of pancreatic cancer remain poorly understood. Here, we employed an epigenetic siRNA library to identify a crucial regulator, ZMYND8, which is involved in glycolysis in PC cells. ZMYND8 was frequently overexpressed in both PC tissues and cell lines, and its elevated expression was significantly correlated with poor overall survival in patients with PC. The high rates of glucose uptake and lactate secretion conferred by ZMYND8 revealed an abnormal activity of aerobic glycolysis in PC cells. Functional studies revealed that ZMYND8 significantly promoted the proliferation, migration and invasion of PC cells. Integrated analyses of CUT&Tag and RNA-seq data revealed that ZMYND8 may activate c-Myc transcriptional activity by modulating downstream epigenetic regulatory pathways. Proteomic profiling and coimmunoprecipitation (Co-IP) assays further demonstrated a direct physical interaction between ZMYND8 and c-Myc. Mechanistic studies revealed that ZMYND8 interacted with and activated c-Myc, thereby promoting the Warburg effect and facilitating PC cell malignancy. Moreover, in vivo studies revealed that overexpression of ZMYND8 resulted in accelerated tumour growth in PC xenografts, which was reversible through the knockdown of c-Myc or treatment with 2-deoxy-D-glucose. Collectively, our data suggest that ZMYND8 functions as a critical metabolic regulator in PC cells by tightly regulating c-Myc activity and may represent a promising novel therapeutic target for advanced pancreatic cancer treatment.

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Fig. 1: Epigenetic siRNA library screening revealed that ZMYND8 promotes glycolysis in PC tissues and cells.
Fig. 2: ZMYND8 enhances aerobic glycolysis in PC cells.
Fig. 3: ZMYND8 promotes the proliferation, migration, and invasion of PC cells.
Fig. 4: ZMYND8 interacts with c-Myc to promote PC glycolysis.
Fig. 5: ZMYND8 enhances the transcriptional activity of c-Myc.
Fig. 6: ZMYND8 promotes the malignant activities of PC cells by regulating aerobic glycolysis through c-Myc.
Fig. 7: ZMYND8 promotes PC tumour growth in vivo.
Fig. 8

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Data availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We are grateful to the Doctors of Guizhou Medical University for their assistance with pancreatic cancer patient tissues collection.

Funding

This work was funded by the National Natural Science Foundation of China (No. 52273256) from KJ, Shenzhen Natural Science Fund (the Stable Support Plan Program (No. 20220810151804002)) from HL, Shenzhen Science and Technology Program (Grant No. RCBS20221008093107027) from ZH.

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Authors and Affiliations

  1. Medical School of Chinese PLA, Beijing, PR China

    Hui Liu, Zhifeng Zhao, Changle Wu & Kai Jiang

  2. Faculty of Hepatopancreatobiliary Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, PR China

    Hui Liu, Zhifeng Zhao, Changle Wu & Kai Jiang

  3. Department of General Surgery, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, PR China

    Hui Liu

  4. Department of Hepatobiliary Surgery, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, Guangdong, PR China

    Jinxin Chen & Zhiwei He

  5. Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical University, Guiyang, PR China

    Zhiwei He

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  1. Hui Liu
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Contributions

HL: Methodology, investigation, and writing original draft. HL, ZH and KJ: Methodology, investigation, and validation. HL, ZZ, CW: Investigation, and validation. HL, ZZ, CW and JC: Validation and formal analysis and resources and data curation. HL, ZH and KJ: Conceptualization, resources, writing-review & Editing, supervision, funding acquisition, and project administration.

Corresponding authors

Correspondence to Zhiwei He or Kai Jiang.

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The authors declare no competing interests.

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The approval of the Institutional Review Board at the Affiliated Hospital of Guizhou Medical University, Guizhou Medical University. All the animal studies were approved by the Shenzhen University Institutional Animal Care and Use Committee.

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Liu, H., Zhao, Z., Wu, C. et al. ZMYND8 promotes the Warburg effect and tumorigenesis through c-Myc activation in pancreatic cancer. Oncogene 44, 3083–3095 (2025). https://doi.org/10.1038/s41388-025-03483-0

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