Integrative analysis identifies targetable CREB1/FoxA1 transcriptional co-regulation as a predictor of prostate cancer recurrence

Abstract

Identifying prostate cancer-driving transcription factors (TFs) in addition to the androgen receptor promises to improve our ability to effectively diagnose and treat this disease. We employed an integrative genomics analysis of master TFs CREB1 and FoxA1 in androgen-dependent prostate cancer (ADPC) and castration-resistant prostate cancer (CRPC) cell lines, primary prostate cancer tissues and circulating tumor cells (CTCs) to investigate their role in defining prostate cancer gene expression profiles. Combining genome-wide binding site and gene expression profiles we define CREB1 as a critical driver of pro-survival, cell cycle and metabolic transcription programs. We show that CREB1 and FoxA1 co-localize and mutually influence each other's binding to define disease-driving transcription profiles associated with advanced prostate cancer. Gene expression analysis in human prostate cancer samples found that CREB1/FoxA1 target gene panels predict prostate cancer recurrence. Finally, we showed that this signaling pathway is sensitive to compounds that inhibit the transcription co-regulatory factor MED1. These findings not only reveal a novel, global transcriptional co-regulatory function of CREB1 and FoxA1, but also suggest CREB1/FoxA1 signaling is a targetable driver of prostate cancer progression and serves as a biomarker of poor clinical outcomes.

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

“…Despite initial treatment responses from treating aggressive primary and metastatic prostate cancer through castration to suppress AR signaling 4 , resistance ensues as 80% of mCRPC tumors harbor either AR gene amplification, amplification of a CRE upstream of AR, or activating AR coding mutations 11,55,62 . Given the AR-dependent 15,18 and AR-independent 25 oncogenic activity of FOXA1 in prostate cancer, its inhibition is an appealing alternative therapeutic strategy. Our dissection of the FOXA1 cis-regulatory landscape complement recent findings by revealing loci that are important for the regulation of FOXA1.…”

“…Independent from its role in AR signaling, FOXA1 also regulates the expression of genes involved in cell cycle regulation in prostate cancer [19][20][21] . For instance, FOXA1 co-localizes with CREB1 to regulate the transcription of genes involved in cell cycle processes, nuclear division, and mitosis in mCRPC [19][20][21][22][23][24][25] . FOXA1 has also been shown to promote feed-forward mechanisms to drive disease progression 26,27 .…”

Blocking Myristoylation of Src Inhibits Its Kinase Activity and Suppresses Prostate Cancer Progression

“…The above cell lines were obtained in September 2013 and were defined as passage 1 (the first thawing) when arrived in the lab. SYF1 (Src −/− Yes −/− Fyn −/− ) mouse fibroblast cell line and LNCaP-abl, and 293T expressing rtTA (293T-rtTA) were gifts from Dr. Jonathan Cooper’s lab in August 2008 (17), Dr. Qianben Wang’s lab in March 2016 (18), and Dr. Kathrin Plath’s lab in May 2008 (12), respectively. Cancer cell lines were cultured in ATCC-recommended medium, and LNCaP-abl was grown in 10% charcoal-stripped fetal calf serum.…”

Keys to unlock androgen receptor translocation

“…Phos-pho-CREB1 regulates expression of many genes, including AR (4) and, in combination with androgen, the AR-target gene, PSA. CREB1 is a driver of survival, cell-cycle, and metabolic transcription programs and co-localizes with FoxA1 on the cistrome in prostate cancer cells (5). Gene expression analyses reveal that CREB1/FoxA1 target genes are predictive of prostate cancer recurrence.…”