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Oxoglutarate dehydrogenase-like inhibits the progression of hepatocellular carcinoma by inducing DNA damage through non-canonical function

Cell Death & Differentiation volume 30, pages 1931–1942 (2023)Cite this article

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Abstract

Oxoglutarate dehydrogenase-like (OGDHL) is considered to be the isoenzyme of oxyglutarate dehydrogenase (OGDH) in the OGDH complex, which degrades glucose and glutamate. OGDHL was reported to reprogram glutamine metabolism to suppress HCC progression in an enzyme-activity-dependent manner. However, the potential subcellular localization and non-canonical function of OGDHL is poorly understood. We investigated the expression of OGDHL and its effect on HCC progression. By employing a variety of molecular biology techniques, we revealed the underlying mechanism of OGDHL-induced DNA damage in HCC cells in vitro and in vivo. AAV loaded with OGDHL exerts therapeutic effect on mouse HCC and prolongs survival time. OGDHL induces DNA damage in HCC cells in vitro and in vivo. We also observed that OGDHL possesses nuclear localization in HCC cells and OGDHL-induced DNA damage was independent of its enzymatic activity. Mechanistically, it was demonstrated that OGDHL binds to CDK4 in the nucleus to inhibit the phosphorylation of CDK4 by CAK, which in turn attenuates E2F1 signaling. Inhibition of E2F1 signaling downregulates pyrimidine and purine synthesis, thereby inducing DNA damage through dNTP depletion. We clarified the nuclear localization of OGDHL and its non-canonical function to induce DNA damage, which demonstrated that OGDHL may serve as a select potential therapeutic target for HCC.

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Fig. 1: OGDHL possesses nuclear localization.
Fig. 2: Increased OGDHL induces DNA damage in HCC cells.
Fig. 3: Intranuclear OGDHL induces DNA damage, independent of its enzyme activity.
Fig. 4: OGDHL mediates dNTP depletion in HCC cells.
Fig. 5: Nuclear OGDHL interacts with CDK4 through its Dehydrogenase, E1 component domain.
Fig. 6: OGDHL suppresses CAK-mediated phosphorylation of CDK4 at Thr172.
Fig. 7: OGDHL inhibits the expression of rate-limiting enzymes of the nucleotide synthesis pathway by targeting CDK4-pRB-E2F1signaling.
Fig. 8: OGDHL inhibits tumor growth and prolongs overall survival in vivo.

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All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (81871967, 82173129).

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Author notes

  1. These authors contributed equally: Xiang Jiang, Jin Peng, Yuanyuan Xie.

Authors and Affiliations

  1. State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China

    Xiang Jiang, Jin Peng, Yuanyuan Xie, Qi Liu, Peng Yan, Ye Wang, Laizhu Zhang, Huan Li, Yunzheng Li, Binghua Li & Decai Yu

  2. Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, 210008, China

    Yanchao Xu & Decai Yu

  3. Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University of Chinese Medicine, Nanjing, 210008, China

    Chunxiao Cheng & Decai Yu

  4. School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, 210096, China

    Shoujing Xu & Junhai Han

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Contributions

Conceptualization: XJ, DY. Project administration: DY. Funding acquisition: DY; performed majority of the experiments and Writing original draft: XJ, YX, QL, YX and JH; Writing – review & editing: XJ, DY, SX; Investigation: CC, YW, LZ; Data curation: HL, YL, BL, JP; Supervision: DY.

Corresponding author

Correspondence to Decai Yu.

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The authors declare no competing interests. The research was approved by Experimental Animal Ethics Committee of Nanjing Hospital Affiliated to Nanjing Medical University (DWSY-2105599).

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Jiang, X., Peng, J., Xie, Y. et al. Oxoglutarate dehydrogenase-like inhibits the progression of hepatocellular carcinoma by inducing DNA damage through non-canonical function. Cell Death Differ 30, 1931–1942 (2023). https://doi.org/10.1038/s41418-023-01186-1

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