Abstract
Breast cancer (BC) remains the leading cause of global female cancer-related mortality, with poor survival in advanced stages driven largely by metastasis. Ubiquitination, a key post-translational modification, critically regulates the stability and function of various proteins, including oncoproteins and tumor suppressors, and deubiquitinases (DUBs) reversing this process are emerging therapeutic targets. In this study, we report that haploid germ cell-specific nuclear protein kinase (HASPIN) is highly expressed in BC and is closely associated with poor prognosis. We identify the DUB Otubain-2 (OTUB2) as a critical regulator of the oncogenic kinase HASPIN in BC. We demonstrate that OTUB2 binds to and deubiquitylates HASPIN, specifically counteracting its K48-linked polyubiquitination and subsequent proteasomal degradation. Acetylation of HASPIN at lysine 751 by acetyltransferase lysine acetyltransferase 5 (KAT5) enhances its affinity for OTUB2, promoting HASPIN stability. Functionally, OTUB2 depletion reduces HASPIN protein levels, while OTUB2 overexpression-induced HASPIN upregulation drives BC cell proliferation and invasion both in vivo and in vitro. These findings establish OTUB2 as a novel DUB for HASPIN and reveal a previously unknown regulatory axis involving KAT5, acetylation, OTUB2, ubiquitination, and HASPIN, which is crucial for BC progression. Consequently, HASPIN acts as an oncogene in BC and represents a promising new therapeutic target for intervention.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 82203745 to JG), The Clinical Research Fund of Collaborative Innovation Center for Individualized Cancer Medicine jointly built by the Ministry and the Province (to MH).
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MH and WS conceived and designed the research; JG and KK conducted the experiment and drafted the paper; SW and ZJ interpreted the data and revised the paper. HL and YZ conducted data analysis.
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Guo, J., Kang, K., Wang, S. et al. KAT5-mediated acetylation enhances the deubiquitination of HASPIN by OTUB2 and promotes breast cancer progression. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08658-5
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DOI: https://doi.org/10.1038/s41419-026-08658-5
