Chromatin and Epigenetic Dysregulation of Prostate Cancer Development, Progression, and Therapeutic Response

Abstract

The dysregulation of chromatin and epigenetics has been defined as the overarching cancer hallmark. By disrupting transcriptional regulation in normal cells and mediating tumor progression by promoting cancer cell plasticity, this process has the ability to mediate all defined hallmarks of cancer. In this review, we collect and assess evidence on the contribution of chromatin and epigenetic dysregulation in prostate cancer. We highlight important mechanisms leading to prostate carcinogenesis, the emergence of castration-resistance upon treatment with androgen deprivation therapy, and resistance to antiandrogens. We examine in particular the contribution of chromatin structure and epigenetics to cell lineage commitment, which is dysregulated during tumorigenesis, and cell plasticity, which is altered during tumor progression.

Keywords: androgen receptor signaling inhibitors; castration resistant prostate cancer; chromatin; chromatin regulators alterations; chromatin-associated factors; drug resistance; epigenetics; lineage commitment; lineage plasticity; prostate cancer.

Figure 1

Epigenetic- and chromatin-related mechanisms with potential for dysregulation in prostate cancer cells. Epigenetic dysregulation can occur at multiple levels, including changes in chromatin accessibility, histone and DNA modification through processes such as methylation, chromatin remodeling, modification of transcription factors and changes in their availability, cis-regulatory elements, chromatin loops, and topologically associated domains. These chromatin and epigenetic features can be analyzed via the integration of multiple high-throughput sequencing data types. These data include chromatin conformation capture (Hi-C) to understand the 3D chromatin structure and topologically associated domains, chromatin immunoprecipitation (ChIP-seq) to study histone markers, assay for transposase-accessible chromatin (ATAC-seq) to show chromatin accessibility patterns, and DNA methylation sequencing. Figure created with BioRender.com.

Figure 2

Epigenetic plasticity in prostate cancer. Epigenetic dysregulation (light blue boxes) is in the forefront of lineage plasticity as well as in carcinogenesis and therapy resistance. Normal prostate epithelium is renewing at a steady state as terminally differentiated luminal cells are slowly replaced by progenitor cells. As genetic alterations accumulate due to cell division and the normal aging process, driver alterations (red boxes) such as ETS gene fusions or SPOP mutations emerge. The mutational processes lead to less ordered chromatin structure, as characterized by chromatin relaxation at distal regulatory regions, alterations in DNA methylation and histone modifications, and dysregulation of higher order chromatin structures, which alters the binding of key TFs such as AR. Some cells gain stem-like properties, leading to increased proliferation capacity and reduced apoptotic rates, which leads to tumor formation over time. The plasticity of the cellular identity is also in a key role during the emergence of treatment resistance as the cancer cells can repurpose differentiation-promoting transcription factors such as AR into regulatory regions supporting developmental gene expression (seen in castration-resistant prostate adenocarcinoma, CRPC), or transdifferentiate into non-luminal, small cell prostate carcinoma or neuroendocrine prostate cancer (NEPC).

Figure 3

Expression changes of 94 recurrently mutated genes coding for chromatin-associated proteins in prostate carcinogenesis and development of treatment resistance. Row-scaled log2 mean expression values for each gene (the rows) are shown in a heatmap for benign prostatic hyperplasia (BPH), untreated prostate cancer (PC), and castration-resistant prostate cancer (CRPC) patient samples. The names of frequently studied genes are shown in bold. Each row is annotated with the disease stage, in which the gene is found to be recurrently mutated (either early stage (PC), late stage (CRPC), or both early and late stage). The rows are also annotated with the functional category of each gene. On the right, two columns show the mutation frequency of the gene in early- and late-stage disease in four categories (0–1%, 1–5%, 5–10%, and >10%).

Figure 4

Forms of epigenetic and chromatin dysregulation in PC. DNA methylation is increased at specific regulatory regions, such as the GSTP1 promoter, but is generally reduced genome-wide. Aberrant histone modifications especially at distal regulatory regions, often harboring binding motifs for key transcription factors (TFs) such as the androgen receptor (AR), shift to a more active state. This also occurs due to the action of transcriptional coactivators and chromatin readers such as BRD4, leading to recruitment of these TFs to previously repressed regions. Loss of CHD1 induces chromatin rewiring, and pioneer factors such as FOXA1 are able to bind to repressed regions and recruit other TFs and histone remodeling complexes. Dysregulation of chromatin accessibility is partly due to increased activity of the SWI/SNF remodeling complex, which shifts the chromatin towards more permissive states, a process termed chromatin relaxation. Figure created with BioRender.com.