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) |