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USP44 Promotes the Tumorigenesis of Prostate Cancer Cells through EZH2 Protein Stabilization

  • Park, Jae Min (Department of Biological Sciences, Inha University) ;
  • Lee, Jae Eun (Department of Biological Sciences, Inha University) ;
  • Park, Chan Mi (Department of Biological Sciences, Inha University) ;
  • Kim, Jung Hwa (Department of Biological Sciences, Inha University)
  • Received : 2018.08.02
  • Accepted : 2018.10.11
  • Published : 2019.01.31

Abstract

Ubiquitin-specific protease 44 (USP44) has been implicated in tumor progression and metastasis across various tumors. However, the function of USP44 in prostate cancers and regulatory mechanism of histone-modifying enzymes by USP44 in tumors is not well-understood. Here, we found that enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 methyltransferase, is regulated by USP44. We showed that EZH2 is a novel target of USP44 and that the protein stability of EZH2 is upregulated by USP44-mediated deubiquitination. In USP44 knockdown prostate cancer cells, the EZH2 protein level and its gene silencing activity were decreased. Furthermore, USP44 knockdown inhibited the tumorigenic characteristics and cancer stem cell-like behaviors of prostate cancer cells. Inhibition of tumorigenesis caused by USP44 knockdown was recovered by ectopic introduction of EZH2. Additionally, USP44 regulates the protein stability of oncogenic EZH2 mutants. Taken together, our results suggest that USP44 promotes the tumorigenesis of prostate cancer cells partly by stabilizing EZH2 and that USP44 is a viable therapeutic target for treating EZH2-dependent cancers.

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Fig. 1. EZH2 interacts with USP44.

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Fig. 2. EZH2 protein is stabilized by USP44.

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Fig. 3. USP44 knockdown activates the expression of EZH2 repressive target genes.

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Fig. 4. USP44 knockdown decreases the tumorigenic abilities of prostate cancer cell lines.

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Fig. 5. USP44 knockdown inhibits the CSC-like properties of prostate cancer cells.

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Fig. 6. USP44 promotes the malignancies of prostate cancer cells through EZH2 stabilization.

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Fig. 7. USP44 stabilizes oncogenic EZH2 mutants.

Acknowledgement

Supported by : National Research Foundation of Korea (NRF)

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