PPP1R14B promotes the progression of prostate cancer by regulating the JAK2/STAT3/AR pathway and alters the sensitivity and resistance to enzalutamide

Abstract

Prostate cancer (PCa) is the tumor with the highest incidence rate among men worldwide. There is still a lack of effective treatment options for metastatic PCa and castration-resistant prostate cancer (CRPC). Protein phosphatase 1 regulatory subunit 14B (PPP1R14B) has been found to be associated with the occurrence and development of various cancers. However, the role and mechanism of PPP1R14B in PCa have not yet been deeply explored. Here, we found that PPP1R14B was highly expressed in PCa tissues and was significantly associated with a higher Gleason score and clinical T stage. Knockdown of PPP1R14B significantly inhibited the proliferation, migration and invasion abilities of PCa cells, while overexpression of PPP1R14B produced the opposite effect. Mechanistic investigations revealed that PPP1R14B mainly regulates the expression of AR through the JAK2/STAT3 pathway and forms a positive feedback loop with STAT3 to promote the progression of PCa, reduce the sensitivity of tumors to enzalutamide, and accelerate the formation of drug resistance. In addition, genistein, a drug screened through virtual drug prediction and molecular alignment, mainly inhibits the expression of STAT3 by targeting PPP1R14B. Moreover, when combined with STAT3-IN-13, it can more effectively curb the malignant ability of PCa and enhance the sensitivity of tumor cells to enzalutamide. In conclusion, these findings reveal the function and mechanism of PPP1R14B in the progression of PCa and the resistance of enzalutamide, indicating that PPP1R14B is a potential target for the treatment of PCa and the prospect of genistein as a therapeutic drug.