Cellular specificity of androgen receptor, coregulators, and pioneer factors in prostate cancer

Abstract

Androgen signalling, through the transcription factor androgen receptor (AR), is vital to all stages of prostate development and most prostate cancer progression. AR signalling controls differentiation, morphogenesis, and function of the prostate. It also drives proliferation and survival in prostate cancer cells as the tumour progresses; given this importance, it is the main therapeutic target for disseminated disease. AR is also essential in the surrounding stroma, for the embryonic development of the prostate and controlling epithelial glandular development. Stromal AR is also important in cancer initiation, regulating paracrine factors that excite cancer cell proliferation, but lower stromal AR expression correlates with shorter time to progression/worse outcomes. The profile of AR target genes is different between benign and cancerous epithelial cells, between castrate-resistant prostate cancer cells and treatment-naïve cancer cells, between metastatic and primary cancer cells, and between epithelial cells and fibroblasts. This is also true of AR DNA-binding profiles. Potentially regulating the cellular specificity of AR binding and action are pioneer factors and coregulators, which control and influence the ability of AR to bind to chromatin and regulate gene expression. The expression of these factors differs between benign and cancerous cells, as well as throughout disease progression. The expression profile is also different between fibroblast and mesenchymal cell types. The functional importance of coregulators and pioneer factors in androgen signalling makes them attractive therapeutic targets, but given the contextual expression of these factors, it is essential to understand their roles in different cancerous and cell-lineage states.

Keywords: androgen receptor; cell specificity; coregulators; pioneer factors.

Figure 1

(A) Schematic of the cellular composition of the benign and cancerous prostate. In normal/benign prostate, the epithelial cells are embedded in a stroma of smooth muscle cells and fibroblasts (normal prostatic fibroblasts; NPFs), as well as other cell types such as immune and vasculature. In cancer, tumour cells develop from the benign epithelial cells, and the stroma changes to become primarily composed of cancer-associated fibroblasts (CAFs). (B) Schematic of basic AR signalling. When activated by testosterone or DHT, AR translocates from the cytoplasm to the nucleus, where it binds to chromatin, interacting with pioneer factors, coregulators, and transcriptional machinery to mediate gene expression. (C) Single-cell RNA-seq analysis of primary prostate cancer, depicting the different cell types present and the level of AR expression (shades of red) (Wu et al. 2021).

Figure 2

Schematic representation of AR expression and function in the epithelial/cancer compartments and stromal compartments based on the information covered in this review. In both benign and cancerous conditions, androgen receptor (AR) signalling is important for both compartments. Represented for the epithelial and stromal compartments are the cell types present, the relative levels of AR, and the main function of AR in each compartment throughout cancer progression.

Figure 3

(A) Schematic of pioneer factor action, depicting binding of pioneer factors and the opening of chromatin to allow AR chromatin interactions and transcription. (B) Pioneer factor expression across cell types. (i) Samples microdissected into cancer/epithelia and stroma in benign, PIN, and cancer from patient samples. (ii) Examples of pioneer factors that are more highly expressed in cancer or stroma. (C) Analysis of pioneer factor expression in different prostatic fibroblast, benign epithelial, and cancerous epithelial cell lines. Data grouped via hierarchical clustering via Pearson correlation. Cell line data used were from GSE66850, GSE47203, GSE47354, GSE68164 (Leach et al. 2014, 2015, Doldi et al. 2015). (D) Analysis of pioneer factor expression in scRNA-seq of the primary prostate, where the size and shade of the circle represent the proportion of expressing cells and the extent of the RNA expressed. (E) Analysis of pioneer factors in metastatic sites (SU2C) (Abida et al. 2019). Heatmap depicts average expression of each gene for each metastatic site. Bone = 73, lymph node (LN) = 115, liver = 39, lung = 7, prostate = 7, adrenal = 1, other sites = 25. The samples investigated at each site include samples that have had either anti-androgen treatment or taxane treatment or are treatment-naïve.

Figure 4

(A) Schematic of coregulators influencing AR signalling grouped into four broad categories of coregulatory action. (B) Heatmap depicting the expression of coregulator/NR-interacting proteins across benign, cancerous, and metastatic PCa samples (GSE3325). Data presented as relative to each row and grouped via hierarchical clustering via Pearson correlation. (C) Venn diagram of coregulator/NR-interacting proteins differentially expressed in CRPC samples compared to hormone-naïve cancers from three datasets (GSE35988, GSE32269, GSE70770). Differential expression set as P < 0.05, +/− 1LFC. The box insert identifies the genes with common differentially expression between all three cohorts. (D) Gene expression analysis of coregulators/NR-interacting proteins in metastatic sites (SU2C) (Abida et al. 2019). Heatmap depicts the average expression of each gene for each metastatic site. Green and blue bars indicate which gene has significantly different expression compared to the other metastatic sites measures (P < 0.05, +/− 2LFC; Green more highly expressed, blue lower expression). Bone = 73, lymph node (LN) = 115, liver = 39, lung = 7, prostate = 7. The samples investigated at each site include samples that have had either anti-androgen treatment or taxane treatment or are treatment-naïve. (E) Analysis of coregulator expression in scRNA- seq of the primary prostate, where the size and shade of the circle represent the proportion of expressing cells and the extent of the RNA expressed. (F) Heatmap depicting the coregulator/NR interacting proteins that are differentially expressed between different cell types in microdissected prostate cancer samples. (G) Heatmap depicting the coregulator/NR interacting and differentially expressed between different cell types; prostatic fibroblast (green), benign epithelial (pink), and cancerous epithelial (yellow) cell lines GSE66850, GSE47203, GSE47354, GSE68164 (Leach et al. 2014, 2015, Doldi et al. 2015).