Histone Demethylase KDM4C Stimulates the Proliferation of Prostate Cancer Cells via Activation of AKT and c-Myc.

Lin Lin,Wang Wang,Kung Kung,Yuh Yuh,Chuu Chuu,Jiang Jiang,Tseng Tseng,Sie Sie,Chen Chen,Tsai Tsai,Shen Shen

doi:10.3390/cancers11111785

Abstract

Our three-dimensional organotypic culture revealed that human histone demethylase (KDM) 4C, a histone lysine demethylase, hindered the acini morphogenesis of RWPE-1 prostate cells, suggesting its potential oncogenic role. Knockdown (KD) of KDM4C suppressed cell proliferation, soft agar colony formation, and androgen receptor (AR) transcriptional activity in PCa cells as well as reduced tumor growth of human PCa cells in zebrafish xenotransplantation assay. Micro-Western array (MWA) analysis indicated that KD of KDM4C protein decreased the phosphorylation of AKT, c-Myc, AR, mTOR, PDK1, phospho-PDK1 S241, KDM8, and proteins involved in cell cycle regulators, while it increased the expression of PTEN. Fluorescent microscopy revealed that KDM4C co-localized with AR and c-Myc in the nuclei of PCa cells. Overexpression of either AKT or c-Myc rescued the suppressive effect of KDM4C KD on PCa cell proliferation. Echoing the above findings, the mRNA and protein expression of KDM4C was higher in human prostate tumor tissues as compared to adjacent normal prostate tissues, and higher KDM4C protein expression in prostate tumors correlated to higher protein expression level of AKT and c-Myc. In conclusion, KDM4C promotes the proliferation of PCa cells via activation of c-Myc and AKT.

Highlights

Epigenetic alterations have been shown to be involved in the development or progression of cancer via regulation of histone modifications
Our study suggests that KDM4C is a novel oncoprotein in prostate cancer (PCa), and that KDM4C promotes the proliferation of PCa cells via activation of c-Myc and AKT signaling
We used a gene array to demonstrate that genes involved in prostate glandular differentiation can serve as prognostic biomarkers for prostate cancer (PCa) [17]

Summary

Introduction

Epigenetic alterations have been shown to be involved in the development or progression of cancer via regulation of histone modifications. Cancers 2019, 11, 1785 histone acetylation or methylation marks promote tumor proliferation [1]. Overexpression, alteration, or mutation of human histone demethylases (KDMs) has been found in many types of cancers [1,2]. Eight KDM families composed of 28 members have been identified [3,4]. The expression of KDM4C is higher in castration-resistant prostate cancer (CRPC) [8]. The gene level of KDM4C is higher in aggressive, basal-like breast cancers [9]. The KDM4C interacts with HIF-1α and is required for breast cancer progression [10]

Methods

Results

Conclusion