Deubiquitylase USP25 prevents degradation of BCR-ABL protein and ensures proliferation of Ph-positive leukemia cells
Deubiquitylase USP25 prevents degradation of BCR-ABL protein and ensures proliferation of Ph-positive leukemia cells
复制标题
DOI：
10.1038/s41388-020-1253-0
复制
发表时间：
2020-03-12
期刊：
影响因子：
8
通讯作者：
Naito, Mikihiko
中科院分区：
文献类型：
--
作者：
Shibata, Norihito;Ohoka, Nobumichi;Naito, Mikihiko
由染色体重排引起的融合基因经常在多种癌细胞中发现。其中一些已知是驱动癌基因，如慢性粒细胞白血病（CML）中的BCR-ABL。这种融合基因的产物是异常蛋白质，通常在细胞中通过称为蛋白质质量控制的机制降解。这表明BCR-ABL蛋白的降解在CML细胞中受到抑制，以确保其增殖活性。在这里，我们表明，泛素特异性蛋白酶25（USP 25）抑制BCR-ABL蛋白的降解细胞携带费城染色体（Ph）。发现USP 25在细胞中靠近BCR-ABL蛋白。利用shRNA介导的基因沉默去除USP 25增加了泛素化的BCR-ABL，并降低了BCR-ABL蛋白的水平。因此，BCR-ABL介导的信号传导和细胞增殖在BCR-ABL阳性白血病细胞中通过USP 25的消耗而受到抑制。我们进一步发现，USP 25的药理学抑制诱导Ph阳性白血病细胞中BCR-ABL蛋白的快速降解，而不管它们对酪氨酸激酶抑制剂的敏感性如何。这些结果表明，USP 25是诱导Ph阳性白血病细胞中致癌BCR-ABL蛋白降解的新靶点。这可能是克服激酶抑制剂耐药性的有效方法。
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.