Login to Access Video or Poster Abstract: MP99-07
Sources of Funding: None

Introduction

The transition from androgen-dependent to castration-resistant prostate cancer (CRPC) is a lethal event of uncertain molecular etiology. The aim of this study was to identify the mechanism that AP4 promotes the proliferation and metastasis of CRPC by upreguating of L-plastin.

Methods

A total of 136 paired PCa and adjacent normal tissues were collected from patients who underwent prostatectomy between 2005 and 2015. The univariate and multivariate Cox regression analyses showed that AP4 expression was independent prognostic factor in patients with prostate cancer (PCa). The EMSA, supershift assays and CHIP-qPCR experiments noted that AP4 directly binds to L-plastin promoter. The in vitro and in vivo experiments were performed.

Results

Previously, we reported that L-plastin is involved in the metastasis of PCa and up-regulated by androgen. Recently, we found that L-plastin is activated even after androgen deprivation, suggesting that androgen-independent factors might regulate its expression. Here, we noted that an androgen-independent factor, which locates in the area close to the transcription initiation site (-216 to +118) of L-plastin promoter, might facilitate the up-regulation of L-plastin. AP4 was then identified as a key transcription activator, which directly binds to L-plastin promoter. The microarray analysis noted that L-plastin is the differentially expressed downstream target gene of AP4. Furthermore, we demonstrated that AP4 upregulated L-plastin expression, which promotes the proliferation and metastatic of CRPC in vitro and in vivo. Importantly, AP4 level was increased in CRPC tissues compared with ASPC. Overexpression of AP4 was significantly correlated with poor survival, Gleason score over 7 and lymph node metastasis in a large cohort of PCa tissues (n=136).

Conclusions

Our study characterizes a new mechanism in CRPC, in which AP4 increases the progression of CRPC through binding L-plastin promoter. Strategies designed to target AP4 may provide novel therapeutic agents for the management of CRPC.

Funding

None