Integrative epigenetic taxonomy of primary prostate cancer

Abstract

The Androgen Receptor (AR) is the key-driving transcription factor in prostate cancer, tightly controlled by epigenetic regulation. To date, most epigenetic profiling has been performed in cell lines or limited tissue samples. Here, to comprehensively study the epigenetic landscape, we perform RNA-seq with ChIP-seq for AR and histone modification marks (H3K27ac, H3K4me3, H3K27me3) in 100 primary prostate carcinomas. Integrative molecular subtyping of the five data streams revealed three major subtypes of which two were clearly TMPRSS2-ERG dictated. Importantly, we identify a third subtype with low chromatin binding and activity of AR, but with high activity of FGF and WNT signaling. While positive for neuroendocrine-hallmark genes, these tumors were copy number-neutral with low mutational burden, significantly depleted for genes characteristic of poor-outcome associated luminal B-subtype. We present a unique resource on transcriptional and epigenetic control in prostate cancer, revealing tight control of gene regulation differentially dictated by AR over three subtypes.

STAT3‐dependent analysis revealsPDK4as independent predictor of recurrence in prostate cancer

“…To further validate this association, we correlated STAT3 expression with KEGG “OXPHOS” and KEGG “Ribosome” signatures derived by ssGSEA (Barbie et al , ) in three additional public PCa data sets. We used The Netherlands Cancer Institute (NCI, n = 91, BioProject: PRJNA494345; GEO: GSE120741) (Stelloo et al , ), the Vancouver Prostate Center (VPC, n = 43, BioProject: PRJEB21092) (Lapuk et al , ; Wyatt et al , ; Akamatsu et al , ; Beltran et al , ; Mo et al , ), and the Russian Academy of Science (RAS, n = 33, BioProject: PRJNA477449) data sets. All three data sets showed a significant negative Pearson correlation of STAT3 log cpm with KEGG “OXPHOS” (Fig EV3B): NCI: ρ = −0.77, adj.…”

“…Samples were ranked according to STAT3 expression and assigned to groups: “high STAT3” consisted of the 1–0.8 th quantile ( n = 100), “low STAT3” of the 0.2 nd quantile ( n = 100), and “medium STAT3” of all samples in between ( n = 298). RNA‐Seq data from The NCI (BioProject: PRJNA494345; GEO: GSE120741) (Stelloo et al , ), the VPC (BioProject: PRJEB21092) (Lapuk et al , ; Wyatt et al , ; Akamatsu et al , ; Beltran et al , ; Mo et al , ), and the RAS (BioProject: PRJNA477449) RNA‐Seq data were downloaded in form of fastq files from the Short Read Archive. Sequencing reads were aligned to the human reference genome (hg38) using STAR (Dobin et al , ).…”

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

“…AR is encoded by a ubiquitously expressed gene located in the X chromosome at Xq11-12 and is particularly important in prostate development and homeostasis (Lubahn et al 1988). When dysregulated, however, AR activity is central to the onset, development and progression to metastasis of prostate cancer (PCa), the most common cancer diagnosed in males worldwide (Matias et al 2000, Gottlieb et al 2004, Knudsen & Penning 2010, Arora & Barbieri 2018, Centenera et al 2018, Cioni et al 2018, Li et al 2018, Nevedomskaya et al 2018, Paschalis et al 2018. In addition, AR mutations are linked to disorders of male sexual differentiation and development termed androgen insensitivity syndromes (AIS) (Hughes et al 2012, Mongan et al 2015, Gibson et al 2018 and to the rare adult-onset hereditary neurodegenerative disorder known as spinal and bulbar muscular atrophy (SBMA or Kennedy's disease; OMIM #313200) (Spada et al 1991, Badders et al 2018, Cortes & La Spada 2018, Lieberman 2018, Pennuto & Rinaldi 2018.…”

“…Among them, about half of the patients with PCa feature fusions of the AR-regulated gene, TMPRSS2, with different fragments of the ETS-related gene (ERG), a member of the ETS family of transcription factors. The presence of these TMPRSS2:ERG fusions defines the predominant molecular subtype of PCa (Yu et al 2010, Park et al 2014, Reig et al 2016, Stelloo et al 2018, Berglund et al 2019. The encoded ERG truncated variants are resistant to degradation and transform the AR from a factor promoting lineage-specific differentiation of the prostate to one that potentiates de-differentiation into a stem celllike state (Yu et al 2010).…”

“…Most notably, the dependence of PCa tumors on the AR protein and its cognate endogenous hormones is the basis for its pharmacological exploitation as a drug target. Indeed, inhibition of AR functions by means of ligand depletion and/or the use of AR antagonists (antiandrogens) is the first line of therapeutic intervention against PCa (Chen et al 2008, Mohler et al 2012, Lorente et al 2015, Aggarwal et al 2017, Ponnusamy et al 2017, Narayanan et al 2018, Nevedomskaya et al 2018. However, recurrent resistant and incurable tumors arise as a result of inappropriately restored AR function associated with various genetic and epigenetic accidents.…”