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The deubiquitinating enzyme USP37 regulates the oncogenic fusion protein PLZF/RARA stability

Oncogene volume 32, pages 5167–5175 (2013)Cite this article

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Abstract

Acute promyelocytic leukemia (APL) is predominantly characterized by chromosomal translocations between the retinoic acid receptor, alpha (RARA) gene and the promyelocytic leukemia (PML) or promyelocytic leukemia zinc finger (PLZF) gene. In APL cells with PML/RARA fusions, arsenic trioxide and all-trans retinoic acid treatments specifically target the fusion protein for proteasome-dependent degradation, thereby promoting cellular differentiation and clinical remission of disease. In contrast, APL cells expressing PLZF/RARA fusion proteins are largely resistant to similar treatments and prognosis for patients with this translocation is poor. Understanding the molecular mechanisms regulating PLZF/RARA protein stability would provide novel therapeutic targets for PLZF/RARA-associated APL. Toward this end, we have performed an RNAi-based screen to identify factors affecting PLZF/RARA stability. Among the factors identified was the ubiquitin-specific peptidase 37 (USP37). We showed that USP37 interacted with PLZF/RARA through the PLZF moiety and sustained PLZF/RARA steady state levels. Domain mapping study revealed that N-terminal domain of USP37 is required for the PLZF/RARA interaction and protein regulation. Furthermore, overexpression or depletion of USP37 caused an increase or decrease of PLZF/RARA protein half-life, correlating with down- or upregulation of PLZF/RARA poly-ubiquitination, respectively. By PLZF/RARA-transduced primary mouse hematopoietic progenitor cells, we demonstrated that Usp37 knockdown alleviated PLZF/RARA-mediated target gene suppression and cell transformation potential. Altogether, our findings of USP37-modulating PLZF/RARA stability and cell transformation suggest that USP37 is a potential therapeutic target for PLZF/RARA-associated APL.

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Acknowledgements

We thank Dr. J Wade Harper for USP37, OTUD6B and USP2 cDNA constructs, Dr Sheng-Chung Lee for anti-ubiquitin antibody, and Dr Yen-Sung Huang for mouse preparation. We also thank for the NRPGM Core RNAi by providing lentiviral constructs for TetOn system and shRNAs of DUBs. We are grateful to Dr Michael J Matunis for comments on the paper. The work was supported by NSC Grants (NSC100-2321-B-001-004; NSC100-3112-B-001-004) and an Academia Sinica Investigator Award to H-M Shih.

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Authors and Affiliations

  1. Molecular Medicine Program, Taiwan International Graduate Program (TIGP), Academia Sinica, Taipei, Taiwan

    W-C Yang & H-M Shih

  2. Institute of Biochemistry and Molecular Biology, School of Life Science, National Yang-Ming University, Taipei, Taiwan

    W-C Yang & H-M Shih

  3. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    W-C Yang & H-M Shih

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  1. W-C Yang
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Correspondence to H-M Shih.

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Yang, WC., Shih, HM. The deubiquitinating enzyme USP37 regulates the oncogenic fusion protein PLZF/RARA stability. Oncogene 32, 5167–5175 (2013). https://doi.org/10.1038/onc.2012.537

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