Background: Prostate cancer (PCa) is the 5th most common cancer overall in the world. Epigenetic alterations have been shown to be involved in the development or progression of cancer via regulation of histone modifications. Methods: In this study, we use the state-of-the-art Micro-Western Array (MWA) for protein profiling study. MWA is a protein array composes of a GeSim Nanoplotter arrayer, a GE multiphor, and a Licor Odyssey infra-red scanner. MWA allows detecting protein expression level or phosphorylation status change of 96-384 different antibodies in 6-15 samples simultaneously but the quantity of samples and antibodies required for MWA is approximately 500-1000 fold less than the conventional Western blotting. We use MWA with 512 antibodies to analyze the human prostatic acinar of RWPE-1 generated prostate epithelial cells in a three-dimensional (3D) basement membrane (BM) that recapitulates the differentiated morphological characteristics and protein expression profile of a human prostate glandular epithelial tissue. Results: We observed 20 up-regulated and 21 down-regulated protein candidates significantly change during RWPE-1 polarization process from cluster to acinar in 3D microenvironment. We applied the acinar morphogenesis-specific protein profile to cohort of patients with prostate cancer (n = 50) and we discovered that 12-protein acinar differentiation-related epigenetic signature can effectively predict the clinical prognosis of prostate cancer recurrent disease after surgery. Among the epigenetic proteins, histone lysine demethylases proteins KDM4A, KDM4B, and KDM4C can modulate androgen receptor (AR)-mediated transcription and share high similarity. However, they exhibit different regulatory effects on cell proliferation, cancer metastasis, and prostate acinar morphogenesis and can be therapeutic targets for PCa. Conclusion: Our study suggests that tissue architecture-specific epigenetic proteins are useful prognostic markers for PCa.
