BACKGROUND: Androgen deprivation therapy (ADT) induces cellular senescence and tumor stasis, thus serving as the standard treatment for prostate cancer (PCa). However, continuous suppression of canonical androgen receptor signaling actually leads to the switch from androgen-responsive growth to androgen-independent growth, contributing to "escape" from this ADT-induced senescence (AIS) and, subsequently, the development of castration-resistant prostate cancer (CRPC). Unfortunately, the mechanism underlying this phenomenon remains elusive. RESULTS: In this study, we demonstrated that androgen receptor splicing variant 7 (ARv7), a dominant factor mediating abnormal AR signaling and ADT resistance, is closely associated with outgrowth from AIS of PCa cells. Mechanistically, ARv7 binds to the promoter of SKP2, activating its transcription, and then promotes the proteasomal degradation of the cell cycle regulator p27 and G1/S transition. In addition, we applied bioinformatic and in vitro analyses to show that SKP2 expression level is dramatically inhibited upon ADT, but its reactivation is one key step during the establishment of CRPC. Finally, we also demonstrated that SKP2 inhibitor treatment can significantly inhibit the growth of androgen-independent cell lines and enhance the efficacy of ADT. CONCLUSIONS: Our work reveals a novel role of ARv7 in regulating AIS and suggests that targeting the ARv7/SKP2/p27 axis could be a potential strategy to delay disease progression to the CRPC state during prolonged ADT.