Fusion genes resulting from chromosomal rearrangements are frequently found in a variety of cancer cells. Some of these are known to be driver oncogenes, such as BCR-ABL in chronic myelogenous leukemia (CML). The products of such fusion genes are abnormal proteins that are ordinarily degraded in cells by a mechanism known as protein quality control. This suggests that the degradation of BCR-ABL protein is suppressed in CML cells to ensure their proliferative activity. Here, we show that ubiquitin-specific protease 25 (USP25) suppresses the degradation of BCR-ABL protein in cells harboring Philadelphia chromosome (Ph). USP25 was found proximal to BCR-ABL protein in cells. Depletion of USP25 using shRNA-mediated gene silencing increased the ubiquitylated BCR-ABL, and reduced the level of BCR-ABL protein. Accordingly, BCR-ABL-mediated signaling and cell proliferation were suppressed in BCR-ABL-positive leukemia cells by the depletion of USP25. We further found that pharmacological inhibition of USP25 induced rapid degradation of BCR-ABL protein in Ph-positive leukemia cells, regardless of their sensitivity to tyrosine kinase inhibitors. These results indicate that USP25 is a novel target for inducing the degradation of oncogenic BCR-ABL protein in Ph-positive leukemia cells. This could be an effective approach to overcome resistance to kinase inhibitors.
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This study was supported, in part, by the Japan Society for the Promotion of Science (KAKENHI Grant Numbers 18K07311 to NS, 16H05090 and 18H05502 to MN), by the Project for Cancer Research and Therapeutic Evolution (P-CREATE) (JP17cm0106522j0002 to NS) from the Japan Agency for Medical Research and Development (AMED), and by the Takeda Science Foundation (to NS). We thank Dr Okabe (Tokyo Medical University) for kindly providing SK-9 cells. We thank Dr Gemma Richards from Edanz Group (www.edanzediting.com/ac) for editing a draft of this paper.
This study was supported, in part, by the Japan Society for the Promotion of Science (KAKENHI Grant Numbers 18K07311 to NS, 16H05090 and 18H05502 to MN), by the Project for Cancer Research and Therapeutic Evolution (P-CREATE) (JP17cm0106522j0002 to NS) from the Japan Agency for Medical Research and Development (AMED), and by the Takeda Science Foundation (to NS).
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Shibata, N., Ohoka, N., Tsuji, G. et al. Deubiquitylase USP25 prevents degradation of BCR-ABL protein and ensures proliferation of Ph-positive leukemia cells. Oncogene 39, 3867–3878 (2020). https://doi.org/10.1038/s41388-020-1253-0
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