Abstract
Simple SummaryChromatin and epigenetic alterations in cancer are responsible for a wide range of transcriptional changes that link DNA mutations to tumor phenotype. In this review, we explore studies describing recurrent epigenetic alterations in prostate cancer and highlight changes that occur during prostate carcinogenesis and progression to lethal treatment-resistant disease.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.
Highlights
Chromatin structure and epigenetics are intertwined but, distinct entities that have been implicated in prostate cancer (PC) disease initiation and progression.Here, we consider epigenetics to be the collection of DNA modifications such as DNA methylation
We studied accessibility between benign prostatic prostatic hymean perplasia (BPH), primary PC, and non-metastatic castration-resistant prostate cancer (CRPC), which revealed that the promoters of expressed genes mostly exhibit accessible chromatin across all sample types, whereas other genomic regions, such as enhancers, exhibit specific accessibility patterns linked to disease stage and display high heterogeneity between individual tumors [72]
Chromatin- and epigenetics-related processes contribute to prostate carcinogenesis and prostate cancer progression to castration-resistance under selective treatment pressure
Summary
Chromatin structure and epigenetics are intertwined but, distinct entities that have been implicated in prostate cancer (PC) disease initiation and progression. Targeted systemic therapies with androgen receptor (AR) signaling inhibitors (ARSIs) such as abiraterone or enzalutamide are primarily used to treat relapsed castration-resistant prostate cancer (CRPC) [3] Employment of these agents has been shown to be effective, especially in high risk primary metastatic HSPCs patients, and their use is becoming more common [4,5]. HSPCs patients, and their use is becoming more common pressure, and cancer growth beyond the tumor microenvironment (TME) Althoughand these combination approaches have demonstrated survival benefits, they colleagues first proposed the concept of epigenetic plasticity, by which have in been to of contribute to theor emergence moreand aggressive castration-realterations theshown structure the chromatin, chromatinofstates, epigenetic alterations sistant be tumors. The plasticity of the cellular identity is in a key role during the emergence of treatment resistance as the cancer cells can repurpose differentiationpromoting 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)
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