Journal
ENDOCRINE-RELATED CANCER
Volume 27, Issue 2, Pages R35-R50Publisher
BIOSCIENTIFICA LTD
DOI: 10.1530/ERC-19-0420
Keywords
prostate cancer; lineage plasticity; androgen receptor; epigenetics; DNA methylation; transcription factor
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Funding
- National Health and Medical Research Council of Australia [1121057]
- Canadian Institutes of Health Research
- Prostate Cancer Foundation
- National Health and Medical Research Council of Australia [1121057] Funding Source: NHMRC
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Tumours adapt to increasingly potent targeted therapies by transitioning to alternative lineage states. In prostate cancer, the widespread clinical application of androgen receptor (AR) pathway inhibitors has led to the insurgence of tumours relapsing with a neuroendocrine phenotype, termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests that this lineage reprogramming is driven largely by dysregulation of the epigenome and transcriptional networks. Indeed, aberrant DNA methylation patterning and altered expression of epigenetic modifiers, such as EZH2, transcription factors, and RNA-modifying factors, are hallmarks of NEPC tumours. In this review, we explore the nature of the epigenetic and transcriptional landscape as prostate cancer cells lose their AR-imposed identity and transition to the neuroendocrine lineage. Beyond addressing the mechanisms underlying epithelial-to-neuroendocrine lineage reprogramming, we discuss how oncogenic signaling and metabolic shifts fuel epigenetic/transcriptional changes as well as the current state of epigenetic therapies for NEPC.
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