Journal Article

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

Jung, Euitaek, Shin, Soon Young, Oh, Sukjin, Jeong, Munki

2023

Overview

Prospero homeobox 1 (PROX1) is a member of the homeobox transcription factor family that plays a critical role in the development of multiple tissues and specification of cell fate. PROX1 expression 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 suppress­ed; 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 human breast cancer cells, suggesting that PROX1 functions as a negative regulator of tumour invasion in MDA-MB-231 cells. Treatment with histone deacetylase (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 protein (AP)-1-binding site located at –734 to –710 in the PROX1 promoter region to suppress PROX1 expression. 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 mechanism 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 regulatory mechanism involved in the suppression of PROX1 expression in breast cancer cells.

• Publisher: Charles University in Prague, First Faculty of Medicine
• Subject: Antibodies / Binding sites / Breast cancer / Breast Neoplasms - genetics / c-Jun protein / Cell fate / Cell Line, Tumor / Cells / DNA methylation / Ectopic expression / Epigenetics / Extracellular matrix / Female / Gene expression / Gene Expression Regulation, Neoplastic / Genes, Homeobox / Histone deacetylase / Histone Deacetylase 1 - genetics / Histone Deacetylase 1 - metabolism / Homeobox / Homeodomain Proteins - genetics / Homeodomain Proteins - metabolism / Humans / Invasiveness / JNK protein / Kinases / MDA-MB-231 Cells / Microscopy / Molecular modelling / Nervous system / Phosphorylation / Prospero protein / Protein expression / Proteins / RNA, Messenger - genetics / Transcription factors / Transcription Factors - genetics / Tumors