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K11- and K29-ubiquitination-mediated nuclear translocation of glycolytic enzyme aldolase A promotes pancreatic cancer progression by NF-κB activation

Cell Death & Differentiation (2025)Cite this article

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Abstract

The function of cytosolic aldolase A (ALDOA) in glycolysis is well recognized. However, the cytosol-to-nucleus redistribution of ALDOA and its nuclear function is poorly understood. Here, we uncover inflammatory factor-stimulated nuclear function of ALDOA in augmenting pancreatic carcinogenesis by activating NF-κB signaling in a ubiquitination-dependent manner. TNF-α-triggered K11- and K29-linked ubiquitination of ALDOA at Lys200 promotes its interaction with RelA/p65 and facilitates importin-β-dependent nuclear translocation, establishing a positive feedback regulation in the tumor microenvironment by elevating the TNF-α expression in pancreatic ductal adenocarcinoma (PDAC). USP4 is identified as a negative regulator that deubiquitinates ALDOA. Instead of broadly targeting ALDOA, which causes glycolysis impairment, the specific elimination of ALDOA ubiquitination enhances chemosensitivity and the synergistic effect of chemotherapy combined with p65-specific anti-inflammatory therapy by selectively suppressing inflammation-induced proliferation in cancer cells. Collectively, we unveil the multifaceted mechanisms by which ALDOA promotes PDAC carcinogenesis, from metabolic to gene regulatory perspectives, providing potential therapies combatting cancer.

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Fig. 1: ALDOA promotes inflammation and tumor progression in PDAC.
Fig. 2: ALDOA interacts with RelA/p65 and upregulates NF-κB signaling activation in response to TNF-α stimulation.
Fig. 3: K11- and K29-linked ubiquitination of ALDOA increases its interaction with p65 in response to TNF-α.
Fig. 4: ALDOA promotes TNF-α-stimulated NF-κB activation in a ubiquitination-dependent manner.
Fig. 5: USP4 deubiquitinates ALDOA and attenuates ALDOA-mediated RelA/p65 activation.
Fig. 6: Suppressed ALDOA-K200 ubiquitination hinders p65-mediated oncogenic processes in PDAC cells.
Fig. 7: The impaired ALDOA-p65 signaling axis attenuates tumor growth in a murine model.

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Data availability

The mass spectrometry proteomics data have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifiers PXD059292 and 10.6019/PXD059292, PXD059293 and 10.6019/PXD059293.

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Acknowledgements

We sincerely thank Prof. Daming Gao from Shanghai Institute of Biochemistry and Cell Biology for providing Flag-ALDOA plasmid, Prof. Chensong Zhang from Xiamen University for providing sg-ALDOA plasmids, Prof. Lingqiang Zhang from Academy of Military Science for providing HA-ubiquitin-mutated plasmids, Prof. Danying Chen from Peking University for providing luciferase reporter plasmids, Prof. Jinfang Zhang from Wuhan University for providing the Myc-tagged MARCH1-11 plasmids, Prof. Chengqi Yi from Peking University for providing ALDOB expressing plasmid, Prof. Jianguo Ji from Peking University for providing MiaPaCa-2 cell line, Prof. Jihui Hao from Tianjin Medical University for providing SW1990 cell line, Prof. Peng Du from Peking University for providing PANC-1 cell line, Prof. Xianghong Yang from Shengjing Hospital of China Medical University for providing HPDE6C7 cell line, Prof. Deng Pan from Tsinghua University for providing Panc02 cell line and Prof. Zhe Zhang from Peking University for providing HEK293F cell line. We thank Dr. Shichen Geng from Peking University for instructing the construction of site-mutation cell lines. We thank the National Center for Protein Sciences and the Core Facilities of Life Sciences at Peking University, particularly Qi Zhang, Wenling Gao, Siying Qin, Liying Du, Huan Yang, Jia Luo, Feifei Cheng, and Guilan Li for technical assistance. We also appreciate Biorender for its easy-to-use platform that helped illustrate our research findings (agreement no. ON28RU2H3S).

Funding

This work was supported by National Key R&D Program of China (2024YFA1306200 and 2022YFA1302803), and the National Natural Science Foundation of China (82130081 and 32270756).

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Authors and Affiliations

  1. State Key Laboratory of Gene Function and Modulation Research, School of Life Sciences, Peking University, Beijing, China

    Siru Zhou, Yulin Li, Chao Wang, Yuhan Zhao & Xiaofeng Zheng

  2. Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing, China

    Siru Zhou, Yulin Li, Chao Wang, Yuhan Zhao & Xiaofeng Zheng

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Contributions

S Zhou and X Zheng designed this study. S Zhou conducted the experiments. S Zhou analyzed the data and wrote the manuscript. Y Li, C Wang and Y Zhao helped the mice xenograft assay. X Zheng supervised this study and wrote the manuscript.

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Correspondence to Xiaofeng Zheng.

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All animal experiments were approved by the Ethics Committee of Peking University (IACUC No. LSC-ZhengXF-1). All animal handling and experimental protocols strictly adhered to the ethical principles outlined in the Declaration of Helsinki, as well as relevant national guidelines and regulations. The human tissue arrays were purchased from Shanghai Superchip Company Ltd. with the ethics approval number (SHXC2021YF01).

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Zhou, S., Li, Y., Wang, C. et al. K11- and K29-ubiquitination-mediated nuclear translocation of glycolytic enzyme aldolase A promotes pancreatic cancer progression by NF-κB activation. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01592-7

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