Abstract 2453: Olfactomedin 4 downregulation enhances MYC-signaling in human benign prostate cells and the Olfm4 mouse models

Abstract

Abstract Prostate cancer is the most diagnosed solid tumor and the second leading cause of cancer related death in American men. We have reported previously that OLFM4 gene expression was reduced or lost during prostate cancer progression due to frequent genetic deletion and hypermethylation of the OLFM4 gene promoter region. To investigate OLFM4 gene biological functions and molecular mechanisms underlying prostate cancer progression, we have established OLFM4 knock out RWPE1 cells and Olfm4 knock out mouse model. Functionally, OLFM4-knockout RWPE1 cells exhibited enhanced proliferation of the stem/progenitor-like cell population and abnormal differentiation. Bulk-cell RNA sequencing analysis pinpointed that MYC expression was enhanced in the OLFM4-knockout RWPE1 cells compared with OLFM4-wild cells. Molecular and signaling pathway studies revealed an increase in the WNT/APC/MYC signaling pathway gene signature and MYC target genes that regulate multiple biological processes in OLFM4-knockout RWPE1 cells and Olfm4-knock out mouse models. To test the function of the MYC gene in RWPE1 cells, we used (+)-JQ1, an MYC inhibitor, in both 2D and 3D culture models and found that (+)-JQ1 substantially inhibited the proliferation of OLFM4-knockout GFP reporter RWPE1 cells compared with OLFM4-W RWPE1 cells in both types of cultures. We further studied MYC inhibitors using organoid culture for Olfm4-/-/TRAMP mouse prostate tumors. These results suggest that OLFM4-negative prostate cancer is more sensitive to MYC inhibitor’s therapeutic approaches. Citation Format: Hongzhen Li, Wenli Liu, Jianqiong Zhu, Kay Chin, Griffin P. Rodgers. Olfactomedin 4 downregulation enhances MYC-signaling in human benign prostate cells and the Olfm4 mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2453.