Edited by Xiao-Fan WangChemoresistance is a leading obstacle in effective management of advanced prostate cancer (PCa). A better understanding of the molecular mechanisms involved in PCa chemoresistance could improve treatment of patients with PCa. In the present study, using immune histochemical, chemistry, and precipitation assays with cells from individuals with benign or malignant prostate cancer or established PCa cell lines, we found that the oncogenic transcription factor pre-B cell leukemia homeobox-1 (PBX1) promotes PCa cell proliferation and confers to resistance against common anti-cancer drugs such as doxorubicin and cisplatin. We observed that genetic PBX1 knockdown abrogates this resistance, and further experiments revealed that PBX1 stability was modulated by the ubiquitin-proteasomal pathway. To directly probe the impact of this pathway on PBX1 activity, we screened for PBX1-specific deubiquitinases (Dubs) and found that ubiquitin-specific peptidase 9 X-linked (USP9x) interacted with and stabilized the PBX1 protein by attenuating its Lys-48 -linked polyubiquitination. Moreover, the USP9x inhibitor WP1130 markedly induced PBX1 degradation and promoted PCa cell apoptosis. The results in this study indicate that PBX1 confers to PCa chemoresistance and identify USP9x as a Dub of PBX1. We concluded that targeting the USP9x/ PBX1 axis could be a potential therapeutic strategy for managing advanced prostate cancer.Prostate cancer (PCa) 4 is a malignant disease developed in the prostate, a gland in the male reproductive system. The epidemiological studies reveal that PCa is one of the most common cancers in men and one of the leading causes of cancer-related deaths worldwide (1). Several treatment modalities have been developed against prostate cancers, including androgen-deprivation therapy, localized radiotherapy and chemotherapy. Currently, androgendeprivation therapy is the standard frontline therapy for advanced PCa patients; nevertheless, most patients will eventually develop resistance and these castration-resistant PCa patients rely on chemotherapy. Unfortunately, this regimen only prolongs modest survival of PCa patients, of which many acquire chemoresistance and eventually evolve to a fatal clinical outcome (1). It is widely believed that molecular and genetic events are key players in the resistance but they are not well defined.Pre-B cell leukemia homeobox-1 (PBX1), a member of the TALE (three-amino acid loop extension) family of atypical homeodomain proteins, is cloned from pre-B cell leukemia (2), our recent study demonstrated that it up-regulates the transcription of ring finger protein 6 and contributes to leukemia chemoresistance (3). However, more and more evidence shows that PBX1 is dysregulated and contributes to proliferation, survival, metastasis, and chemoresistance in various solid tumors, including breast, lung, gastric, and ovarian cancers. For example, high expression of PBX1 drives breast cancer proliferation and metastasis by regulating the estrogen receptor transcriptional re...
Chronic myelogenous leukemia (CML) is a clonal malignancy of hematopoietic stem cells featured with the fusion protein kinase BCR-ABL. To elicit the mechanism underlying BCR-ABL stability, we perform a screen against a panel of deubiquitinating enzymes (DUBs) and find that the ubiquitin-specific protease 7 (USP7) drastically stabilizes the BCR-ABL fusion protein. Further studies show that USP7 interacts with BCR-ABL and blocks its polyubiquitination and degradation. Moreover, USP7 knockdown triggers BCR-ABL degradation and suppresses its downstream signaling transduction. In line with this finding, genetic or chemical inhibition of USP7 leads to BCR-ABL protein degradation, suppresses BCR/ABL signaling, and induces CML cell apoptosis. Furthermore, we find the antimalarial artesunate (ART) significantly inhibits USP7/BCR-ABL interaction, thereby promoting BCR-ABL degradation and inducing CML cell death. This study thus identifies USP7 as a putative Dub of BCR-ABL and provides a rationale in targeting USP7/BCR-ABL for the treatment of CML.
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