RRC ID 81462
Author Shibata N, Ohoka N, Tsuji G, Demizu Y, Miyawaza K, Ui-Tei K, Akiyama T, Naito M.
Title Deubiquitylase USP25 prevents degradation of BCR-ABL protein and ensures proliferation of Ph-positive leukemia cells.
Journal Oncogene
Abstract 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.
Volume 39(19)
Pages 3867-3878
Published 2020-5-1
DOI 10.1038/s41388-020-1253-0
PII 10.1038/s41388-020-1253-0
PMID 32203161
MeSH Cell Proliferation / drug effects Deubiquitinating Enzymes / genetics Drug Resistance, Neoplasm / genetics Gene Silencing / drug effects Genes, abl / genetics* Humans Jurkat Cells K562 Cells Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics* Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology Philadelphia Chromosome* Protein Kinase Inhibitors / pharmacology Proteolysis / drug effects RNA, Small Interfering / genetics Ubiquitin Thiolesterase / genetics*
Resource
DNA material CS-RfA-EG (RDB04391) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394)