TRIM25 degrades BRD7 protein stability through the ubiquitin proteasome pathway to promote breast cancer progression and paclitaxel resistance by activating YB1/Bcl-2 transcription axis.

Paclitaxel (PTX) is one of the most common chemotherapeutic drugs for treating breast cancer (BC), but resistance to PTX chemotherapy remains the major cause of treatment failure in BC patients. Our previous studies demonstrated that BRD7 participates in the paclitaxel-mediated chemotherapy sensitization and inhibits the malignant progression of breast cancer. Furthermore, TRIM25 was screened by IP-MS as a potential E3 ubiquitin ligase interacting with BRD7. Nevertheless, the functions and mechanisms of TRIM25 in the malignant progression of breast cancer and PTX resistance, as well as its regulatory relationship with BRD7, are still not clear. Our investigation revealed that TRIM25 effectively promoted cell proliferation, cell cycle progression, and paclitaxel chemoresistance of BC cells. Mechanistically, TRIM25 interacted with BRD7, and the PRYSPRY region of TRIM25 bond to the N-terminal region of BRD7. Additionally, TRIM25 decreased the protein stability of BRD7 through the ubiquitin proteasome pathway by increasing the K48-linked ubiquitination of BRD7 at the K119 site, and then activated the YB1/Bcl-2 signal axis, thus mediating malignant progression and PTX resistance of breast cancer. We further demonstrated that restoration of BRD7 rescued the inhibitory effect of TRIM25 knockdown on the malignant progression and PTX resistance of BC cells. Furthermore, high expression of TRIM25 was found in clinical breast cancer tissues compared to noncancerous breast tissues, which was positively associated with poor prognosis in BC patients. The expression of TRIM25 was negatively correlated with BRD7 expression, and the combined expression of TRIM25 and BRD7 might be a potential molecular marker for the prediction of malignant progression and prognosis of breast cancer. Our findings demonstrate that targeting the TRIM25/BRD7/YB1/Bcl-2 signal axis might be a potential therapeutic strategy for the treatment of breast cancer.