Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Kanagawa, 210-9501, Japan.
Division of Organic Chemistry, National Institute of Health Sciences, Kanagawa, 210-9501, Japan.
Oncogene. 2020 May;39(19):3867-3878. doi: 10.1038/s41388-020-1253-0. Epub 2020 Mar 12.
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.
融合基因是染色体重排的结果，经常在各种癌细胞中发现。其中一些已知是驱动癌基因，如慢性髓系白血病（CML）中的 BCR-ABL。这些融合基因的产物是异常蛋白质，通常在细胞中通过一种称为蛋白质质量控制的机制被降解。这表明在 CML 细胞中，BCR-ABL 蛋白的降解受到抑制，以确保其增殖活性。在这里，我们表明泛素特异性蛋白酶 25（USP25）在携带费城染色体（Ph）的细胞中抑制 BCR-ABL 蛋白的降解。在细胞中发现 USP25 靠近 BCR-ABL 蛋白。使用 shRNA 介导的基因沉默耗尽 USP25 会增加 BCR-ABL 的泛素化，并降低 BCR-ABL 蛋白的水平。因此，通过耗尽 USP25，BCR-ABL 阳性白血病细胞中的 BCR-ABL 介导的信号和细胞增殖受到抑制。我们进一步发现，无论 Ph 阳性白血病细胞对酪氨酸激酶抑制剂的敏感性如何，USP25 的药理学抑制均可诱导 BCR-ABL 蛋白在 Ph 阳性白血病细胞中的快速降解。这表明 USP25 是诱导 Ph 阳性白血病细胞中致癌性 BCR-ABL 蛋白降解的一个新靶点。这可能是克服激酶抑制剂耐药性的有效方法。
