Abstract
Chemoresistance 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.
Highlights
Chemoresistance is a leading obstacle in effective management of advanced prostate cancer (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 demonstrated that targeting the ubiquitin-specific peptidase 9 X-linked (USP9x)/PBX1 axis could be a potential modality to overcome PCa chemoresistance
Summary
PBX1 is highly expressed in PCa tissues and is associated with PCa chemoresistance. PBX1 has been demonstrated to confer to chemoresistance in both breast cancer [12] and leukemia [3], but it was not well known in PCa. The results showed that overexpression of USP9x significantly decreased the ubiquitination levels of PBX1 in PCa cells, and when USP9x was knocked down by its specific siRNA, the polyubiquitination level on PBX1 was markedly increased (Fig. 6D), which suggested that USP9x modulates PBX1 ubiquitination. Consistent with these findings, WP1130 at 10 M or cisplatin at 40 M only induced a marginal cleavage of PARP in PBX1-expressing PC3 cells (Fig. 7, D and E), when this cell line was treated with WP1130 in combination with cisplatin, PARP cleavage was significantly induced (Fig. 7E) These results suggested that targeting at the USP9x/PBX1 axis could be a potential therapeutic modality to overcome chemoresistance in PCa patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
