Login to Access Video or Poster Abstract: MP99-04
Sources of Funding: This work was supported by National Natural Science Foundation of China (81372728, 81572503).

Introduction

Metastasis is the primary cause of cancer-specific death in patients with prostate cancer (PCa). Previous studies identified promoter methylation is responsible for the repression of the tumor metastasis-suppressor gene collapsing response mediator protein-4 (CRMP4) in metastatic PCa. However, the underlying mechanisms for promoter methylation remain unknown.

Methods

In this study, calpain-2 expression in prostatic benign and cancer tissues was determined using immunohistochemistry (IHC). The effects of truncated-CRMP4 by calpain-2 in migration and invasion of PCa cells and the underlying mechanisms were explored. The role of nuclear factor-kappaB (NF-kB) in CRMP4 promoter methylation was evaluated. In addition, the downstream signaling regulated by CRMP4 were determined.

Results

Calpain-2 was differentially upregulated in metastatic PCa Calpain-2 was differentially upregulated in metastatic PCa tissues. N-terminally truncated-CRMP4 by calpain-2 enhanced the ability of migration and invasion via nuclear translocation and subsequently activation of E2F1-mediated DNA methyltransferase 1 (DNMT1) expression. In addition, NF-kB RelA/p65 recruited DNMT1 to directly bind to and methylate the CRMP4 promoter in which Serine276 phosphorylation of p65 was essential. Furthermore, CRMP4 CRMP4 exhibited anti-metastatic function by inhibiting the expression of vascular endothelial growth factor C (VEGFC) via Sema3B- Neuropilin2 signaling.

Conclusions

Calpain-mediated cleavage of CRMP4 promotes PCa metastasis by suppression of CRMP4 transcription via nuclear translocation of N-terminally truncated fragment and subsequent activation of E2F1/NF-kB/DNMT1 signaling which in turn enhanced CRMP4 promoter hypermethylation. Targeting re-expression of CRMP4 may be of great significance in the treatment of patients with metastatic PCa.

Funding

This work was supported by National Natural Science Foundation of China (81372728, 81572503).