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A targetable MYBL2-ATAD2 axis governs cell proliferation in ovarian cancer

Cancer Gene Therapy volume 30, pages 192–208 (2023)Cite this article

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Abstract

The chromatin-modifying enzyme ATAD2 confers oncogenic competence and proliferative advantage in malignances. We previously identified ATAD2 as a marker and driver of cell proliferation in ovarian cancer (OC); however, the mechanisms whereby ATAD2 is regulated and involved in cell proliferation are still unclear. Here, we disclose that ATAD2 displays a classical G2/M gene signature, functioning to facilitate mitotic progression. ATAD2 ablation caused mitotic arrest and decreased the ability of OC cells to pass through nocodazole-arrested mitosis. ChIP-seq data analyses demonstrated that DREAM and MYBL2-MuvB (MMB), two switchable MuvB-based complexes, bind the CHR elements in the ATAD2 promoter, representing a typical feature and principle mechanism of the periodic regulation of G2/M genes. As a downstream target of MYBL2, ATAD2 deletion significantly impaired MYBL2-driven cell proliferation. Intriguingly, ATAD2 silencing also fed back to destabilize the MYBL2 protein. The significant coexpression of MYBL2 and ATAD2 at both the bulk tissue and single-cell levels highlights the existence of the MYBL2-ATAD2 signaling in OC patients. This signaling is activated during tumorigenesis and correlated with TP53 mutation, and its hyperactivation was found especially in high-grade serous and drug-resistant OCs. Disrupting this signaling by CRISPR/Cas9-mediated ATAD2 ablation inhibited the in vivo growth of OC in a subcutaneous tumor xenograft mouse model, while pharmacologically targeting this signaling with an ATAD2 inhibitor demonstrated high therapeutic efficacy in both drug-sensitive and drug-resistant OC cells. Collectively, we identified a novel MYBL2-ATAD2 proliferative signaling axis and highlighted its potential application in developing new therapeutic strategies, especially for high-grade serous and drug-resistant OCs.

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Fig. 1: ATAD2 displays a G2/M gene signature.
Fig. 2: ATAD2 facilitates mitotic progression in ovarian cancer.
Fig. 3: ATAD2 is transactivated by MYBL2.
Fig. 4: ATAD2 is essential for MYBL2-driven cell proliferation in ovarian cancer.
Fig. 5: Loss of ATAD2 decreases the MYBL2 protein stability.
Fig. 6: Coexpression of MYBL2 and ATAD2 at both the bulk tissue and single-cell levels in ovarian cancer patients.
Fig. 7: Hyperactivation of the MYBL2-ATAD2 signaling in high-grade serous, TP53-mutant and drug-resistant OCs.
Fig. 8: Disrupting the MYBL2-ATAD2 signaling by ATAD2 ablation inhibits ovarian cancer growth in vivo.
Fig. 9: Pharmacological inhibition of the MYBL2-ATAD2 axis destroys both drug sensitive and resistant OCs.
Fig. 10: Schematic diagram for the role and mechanism of the MYBL2-ATAD2 signaling in cancer proliferation.

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Acknowledgements

This work was financially supported by grants from the National Natural Science Foundation of China (No. 82002754 and 82172913).

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  1. These authors contributed equally: Qun Liu, Heshu Liu.

Authors and Affiliations

  1. Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, 100006, Beijing, China

    Qun Liu & Jinwei Miao

  2. Department of Obstetrics and Gynecology, Beijing Anzhen Hospital, Capital Medical University, 100029, Beijing, China

    Qun Liu

  3. Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, 100020, Beijing, China

    Heshu Liu, Xuying Huang, Xiaona Fan, Zeru Xiao, Rui Yan, Jiannan Yao, Guanyu An, Yang Ge & Jian Liu

  4. Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, 100020, Beijing, China

    Jian Liu

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Contributions

JL, JM, and YG designed and conceived the study. QL, HL, and XH performed the experiments and generated the majority of the data. XF, ZX, RY, JY, and GA interpreted the data. QL and HL performed the bioinformatics analyses. QL and JL drafted the manuscript. JL and JM reviewed and edited the manuscript. All authors have read and approved the final version of this manuscript.

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Correspondence to Yang Ge, Jinwei Miao or Jian Liu.

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Liu, Q., Liu, H., Huang, X. et al. A targetable MYBL2-ATAD2 axis governs cell proliferation in ovarian cancer. Cancer Gene Ther 30, 192–208 (2023). https://doi.org/10.1038/s41417-022-00538-2

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