SETD1A Promotes Proliferation of Castration-Resistant Prostate Cancer Cells via FOXM1 Transcription.

Liu Yang,Sung Jean Park,Mingli Jin,Kwang Won Jeong,Seung-Yong Seo

doi:10.3390/cancers12071736

Abstract

Androgen deprivation therapy eventually leads to the development of castration-resistant prostate cancer (CRPC). Here, we demonstrate for the first time that the histone H3K4 methyltransferase SETD1A is a major regulator for the proliferation of metastatic CRPC (mCRPC). The expression of SETD1A was significantly correlated with the survival rate of patients with prostate cancer. SETD1A, which is expressed at a higher level in mCRPC than in primary prostate cancer cells, promotes the expression of FOXM1, a gene encoding a cell proliferation-specific transcription factor. SETD1A is recruited to the promoter region of FOXM1 (forkhead box M1) upon binding to E2F1, a protein that regulates the transcription of FOXM1 and contributes to the trimethylation of H3K4 in the FOXM1 promoter region. In addition, SETD1A is essential for the expression of stem cell factor (e.g., OCT4, octamer-binding transcription factor 4) and stem cell formation in mCRPC, suggesting the importance of SETD1A expression in mCRPC tumor formation. Notably, poor prognosis is associated with high expression of the SETD1A–FOXM1 pair in clinical data sets. Therefore, our study suggests that SETD1A plays an important role in the proliferation of mCRPC by regulating FOXM1 transcription.

Highlights

As the androgen receptor (AR) pathway is critical for the progression and development of prostate cancer, androgen deprivation, which leads to the blockage of AR activity, is an effective therapy for the initial treatment of prostate cancer
We examined the expression of SETD1A in prostate cancer tissue
Patients with high SETD1A expression showed lower relapse-free survival (RFS) compared to patients with low SETD1A expression (Figure 1B). These findings suggested the clinical relevance of SETD1A in prostate cancer and led us to assume that SETD1A may play a pivotal role in the progression of prostate cancer

Summary

Introduction

As the androgen receptor (AR) pathway is critical for the progression and development of prostate cancer, androgen deprivation, which leads to the blockage of AR activity, is an effective therapy for the initial treatment of prostate cancer. Patients invariably relapse and eventually develop castration resistance [1,2]. Metastatic castration-resistant prostate cancer (mCRPC) is related to a worse prognosis and is known to be clinically incurable [3,4]. Deciphering the underlying mechanism for castration resistance is critical and may provide a foundation for developing future therapeutic options for mCRPC. Many previous studies have attempted to find target molecules for CRPC therapy. GATA2 (GATA-binding protein 2) and FOXA1 (forkhead box A1) have been proposed as important regulators of AR splice variant-driven transactivation that has been shown to be associated with

Methods

Results

Conclusion