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RAB3D/MDM2/β-catenin/c-MYC axis exacerbates the malignant behaviors of acute myeloid leukemia cells in vitro and in vivo

Cancer Gene Therapy volume 30, pages 335–344 (2023)Cite this article

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Abstract

RAB3D, a small Ras-like GTPase involved in regulating secretory pathway, plays a cancer-promoting role in several solid tumors. However, its role in leukemogenesis remains unknown yet. Acute myeloid leukemia (AML) is a common acute leukemia with a high mortality. Here, we found the higher expression of RAB3D in bone marrow mononuclear cells derived from AML patients (n = 54) versus healthy participants (n = 20). The following loss- and gain-of-function experiments demonstrated that RAB3D promoted growth, enhanced colony formation and accelerated G1/S transition of U937, THP-1 and KG-1 AML cells. RAB3D silencing inhibited tumorigenesis of AML cells in vivo and delayed AML cells-induced death of mice. Interestingly, the expression of RAB3D is positively correlated with that of an oncogene mouse double minute 2 (MDM2) in bone marrow mononuclear cells of AML patients (r = 0.923, p < 0.001). Intracellular MDM2 was conjugated with more ubiquitins and degraded faster when RAB3D was silenced. A commonly therapeutic target of AML, β-catenin signaling, was activated by RAB3D overexpression, but deactivated after MDM2 was silenced. The RAB3D-induced proliferation acceleration and β-catenin activation were abolished by MDM2 knockdown, implying that RAB3D function by stabilizing MDM2. In addition, c-MYC, a β-catenin downstream effector, was recruited directly to the RAB3D gene promoter (-360/-349 and -136/-125 sites) and induced its transcription. Collectively, this study demonstrates that RAB3D may exacerbate the malignant behaviors of AML cells through forming a positive feedback loop with MDM2/β-catenin/c-MYC signaling. RAB3D might be a novel target of clinical AML treatment.

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Fig. 1: RAB3D was upregulated in AML specimens.
Fig. 2: RAB3D facilitated the growth of AML cells in vitro.
Fig. 3: RAB3D promoted malignancy of AML cells in vivo.
Fig. 4: RAB3D activated β-catenin signaling pathway in AML cells.
Fig. 5: RAB3D blocked the ubiquitination and degradation of MDM2 in AML cells.
Fig. 6: The effects of RAB3D on AML cells were antagonized by MDM2 knockdown.
Fig. 7: The transcription of RAB3D was activated by c-MYC.

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Data availability

All the data supporting the findings of this study are included in the article and its supplementary files, and are available from the corresponding author upon reasonable request.

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Acknowledgements

This study was supported by the Youth Fund Project of the National Natural Science Foundation of China (81600133) and the Basic Research and Cultivation Fund for Young Teachers of Zhengzhou University (JC21854036).

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  1. Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China

    Jian Liu, Yumiao Mai, Yingjie Wang, Zhiwei Chen, Huixia Wei & Qianghua Yao

  2. Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China

    Fei Wang

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JL designed the project, and conducted the experiments. YW, WM, ZC, HW, and QY synergistically completed the experiments and data analysis. JL drafted the manuscript. All authors read the manuscript and approved the submission.

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Correspondence to Jian Liu.

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Liu, J., Mai, Y., Wang, Y. et al. RAB3D/MDM2/β-catenin/c-MYC axis exacerbates the malignant behaviors of acute myeloid leukemia cells in vitro and in vivo. Cancer Gene Ther 30, 335–344 (2023). https://doi.org/10.1038/s41417-022-00549-z

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