We have previously reported that lost or reduced olfactomedin 4 (OLFM4) expression is caused by deletions within the OLFM4 gene in 10-25% of all human prostate-cancer samples, and that its expression is lost in more than 58% of advanced prostate-cancer samples. Therefore, we sought to study the role of epigenetic factors in the regulation of OLFM4 gene expression in normal prostate, as well as prostate-cancer, cell lines. Pyrosequencing of genomic DNA extracted from normal prostate or prostate-cancer tissue cells demonstrated that three of the eight CpG sites in the OLFM4 gene promoter were significantly hypermethylated in prostate cancer compared with normal tissue. Exposure to the methylation inhibitor 5-azadeoxycytidine (5-Aza 5 μM) significantly increased OLFM4 expression in RWPE1 benign prostate cells. Knockdown of OLFM4 expression in RWPE benign prostate cells reduced autophagy and enhanced the epithelial-mesenchymal transition (EMT). Restoration of OLFM4 expression in metastatic prostate-cancer cells lacking OLFM4 inhibited cell growth in both in vitro culture models and an in vivo xenograft tumor model, and also inhibited EMT marker gene expression in these cells. 5-Aza induced OLFM4 expression in PC-3 prostate cancer cells and OLFM4 shRNA transfected PC-3 cells affects 5-Aza mediated cell proliferation compared to control-shRNA transfected PC-3 cells. Taken together, our results suggest that OLFM4 inhibits the EMT program in both normal prostate and prostate-cancer cells, and may play a critical role in regulating the EMT program during the progression of cancer. They also suggest that modulation of OLFM4 expression might be a novel molecular target for advancing prostate-cancer therapies.

Citation Format: Hongzhen Li, Wenli Liu, Jianqiong Zhu, Kay Chin, Jaime Rodriguez-Canales, Griffin P. Rodgers. Olfactomedin 4 downregulation is associated with enhancing epithelial-mesenchymal transition in human benign prostate cells and prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 861. doi:10.1158/1538-7445.AM2017-861