Deubiquitylase USP25 prevents degradation of BCR-ABL protein and ensures proliferation of Ph-positive leukemia cells

• Published in: Oncogene Vol. 39; no. 19; pp. 3867 - 3878
• Main Authors: Shibata, Norihito, Ohoka, Nobumichi, Tsuji, Genichiro, Demizu, Yosuke, Miyawaza, Keiji, Ui-Tei, Kumiko, Akiyama, Tetsu, Naito, Mikihiko
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.05.2020; Nature Publishing Group
• Subjects: 13/89; 13/95; 631/67/1990/283/1896; 631/80/474/582; 82/29; 82/80; Apoptosis; BCR-ABL protein; Cell Biology; Cell fusion; Cell proliferation; Cell Proliferation - drug effects; Chromosome rearrangements; Chronic myeloid leukemia; Degradation; Deubiquitinating Enzymes - genetics; Drug Resistance, Neoplasm - genetics; Fusion protein; Gene silencing; Gene Silencing - drug effects; Genes, abl - genetics; Genetic engineering; Human Genetics; Humans; Internal Medicine; Jurkat Cells; K562 Cells; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Medicine; Medicine & Public Health; Myeloid leukemia; Oncology; Philadelphia Chromosome; Proteases; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Proteins; Proteolysis - drug effects; Quality control; RNA, Small Interfering - genetics; Tyrosine; Ubiquitin; Ubiquitin Thiolesterase - genetics; Ubiquitin-specific proteinase; Japan; Pennsylvania
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-020-1253-0

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.