Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer

Stanley Zhou,Shadrielle M G Espiritu,James R Hawley,Ken J Kron,Trevor J Pugh,Junjie Hua ,Tesa Severson ,Seyed Ali Madani Tonekaboni,Hwa Young Yun,Mona Teng,Giacomo Grillo,Theodorus Van Der Kwast,Christopher Arlidge,Fraser Soares,Parisa Mazrooei,Musaddeque Ahmed,Julie Livingstone,Housheng Hansen He,Takafumi N Yamaguchi,Vincent Huang,Wilbert Zwart,Yanyun Zhu,Sarina Cameron,Robert G Bristow,Alex Murison,Paul C Boutros,Michael Fraser,Mathieu Lupien

doi:10.1038/s41467-020-14318-9

Abstract

Prostate cancer is the second most commonly diagnosed malignancy among men worldwide. Recurrently mutated in primary and metastatic prostate tumors, FOXA1 encodes a pioneer transcription factor involved in disease onset and progression through both androgen receptor-dependent and androgen receptor-independent mechanisms. Despite its oncogenic properties however, the regulation of FOXA1 expression remains unknown. Here, we identify a set of six cis-regulatory elements in the FOXA1 regulatory plexus harboring somatic single-nucleotide variants in primary prostate tumors. We find that deletion and repression of these cis-regulatory elements significantly decreases FOXA1 expression and prostate cancer cell growth. Six of the ten single-nucleotide variants mapping to FOXA1 regulatory plexus significantly alter the transactivation potential of cis-regulatory elements by modulating the binding of transcription factors. Collectively, our results identify cis-regulatory elements within the FOXA1 plexus mutated in primary prostate tumors as potential targets for therapeutic intervention.

Highlights

Prostate cancer is the second most commonly diagnosed malignancy among men worldwide
We find that FOXA1 mRNA is consistently the most abundant in prostate tumors compared with 25 other cancer types across patients (Fig. 1a), ranking in the 95th percentile for 492 of 497 prostate tumors profiled in The Cancer Genome Atlas (TCGA) (Supplementary Fig. 1a)
Despite FOXA1 being recurrently mutated[5,6,7,8,11] and playing potent oncogenic roles in prostate cancer etiology[9,10,13], the cis-regulatory elements (CREs) involved in its transcriptional regulation are poorly understood

Summary

Introduction

Prostate cancer is the second most commonly diagnosed malignancy among men worldwide. Our results identify cis-regulatory elements within the FOXA1 plexus mutated in primary prostate tumors as potential targets for therapeutic intervention. Sequencing efforts identified coding somatic single-nucleotide variants (SNVs) mapping to FOXA1 in up to 9%5–10 and 13%9–11 of primary and mCRPC patients, respectively These coding somatic SNVs target the Forkhead and transactivation domains of FOXA112, altering its pioneering functions to promote prostate cancer development[10,13]. By measuring contact frequencies between loci through the use of chromatin conformation capture-based technologies, it enables the identification of regulatory plexuses corresponding to sets of CREs in contact with each other[31,32] By leveraging these technologies, we can begin to understand the three-dimensional organization of the prostate cancer genome and delineate the FOXA1 regulatory plexus. We further show that SNVs mapping to these CREs are capable of altering their transactivation potential, likely through modulating the binding of key prostate cancer TFs

Methods

Results

Conclusion