Homeobox Protein PROX1 Expression is Negatively Regulated by Histone Deacetylase 1 and c-JUN Complex in MDA-MB-231 Human Breast Cancer Cells

Prospero homeobox 1 (PROX1) is a mem-ber of the homeobox transcription factor family that plays a critical role in the development of multiple tissues and specification of cell fate. PROX1 expres-sion is differentially regulated based on the cellular context and plays an antagonistic role as a tumour promoter or suppressor in different tumour types. In human breast cancer, PROX1 expression is suppress-ed; however, the molecular mechanism by which it is down-regulated remains poorly understood. Here, we show that ectopic expression of PROX1 reduces the motility and invasiveness of MDA-MB-231 hu-man breast cancer cells, suggesting that PROX1 func-tions as a negative regulator of tumour invasion in MDA-MB-231 cells. Treatment with histone deacety-lase (HDAC) inhibitors up-regulates PROX1 mRNA and protein expression levels. Knockdown of HDAC1 using short hairpin RNA also up-regulates PROX1 mRNA and protein expression levels. We found that HDAC1 interacted with c-JUN at the activator pro-tein (AP)-1-binding site located at -734 to -710 in the PROX1 promoter region to suppress PROX1 expres-sion. In addition, c-JUN N-terminal kinase-mediated c-JUN phosphorylation was found to be crucial for silencing PROX1 expression. In conclusion, PROX1 expression can be silenced by the epigenetic mecha-nism involved in the complex formation of HDAC1 and c-JUN at the AP-1 site in the PROX1 promoter region in MDA-MB-231 human breast cancer cells. Therefore, this study revealed the epigenetic regula-tory mechanism involved in the suppression of PROX1 expression in breast cancer cells.