The epigenetic and transcriptional landscape of neuroendocrine prostate cancer
Alastair Davies1,2, Amina Zoubeidi1,2, Luke A Selth3,4
1Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
Abstract:
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.
Insights
Prostate cancer tumours can switch to a neuroendocrine phenotype (NEPC) when treated with AR pathway inhibitors. This reprogramming involves epigenetic and transcriptional changes, offering new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Epigenetics
Background:
- Prostate cancer often develops resistance to androgen receptor (AR) pathway inhibitors.
- Tumour cells can adapt by transitioning to alternative lineage states, such as neuroendocrine prostate cancer (NEPC).
- This lineage plasticity is increasingly recognized as a major challenge in cancer therapy.
Purpose of the Study:
- To explore the epigenetic and transcriptional landscape driving prostate cancer lineage reprogramming.
- To understand the mechanisms underlying the transition from AR-dependent to neuroendocrine phenotypes.
- To discuss the role of oncogenic signaling, metabolic shifts, and epigenetic therapies in NEPC.
Main Methods:
- Review of current literature on prostate cancer lineage plasticity.
- Analysis of epigenetic and transcriptional alterations in NEPC.
- Discussion of oncogenic pathways and metabolic reprogramming in NEPC development.
Main Results:
- Dysregulation of the epigenome and transcriptional networks drives NEPC.
- Aberrant DNA methylation and altered expression of epigenetic modifiers (e.g., EZH2) are hallmarks of NEPC.
- Oncogenic signaling and metabolic shifts contribute to epigenetic and transcriptional changes.
Conclusions:
- Understanding the epigenetic and transcriptional basis of NEPC is crucial for developing effective treatments.
- Targeting epigenetic modifiers and related pathways holds promise for NEPC therapy.
- Further research into lineage reprogramming mechanisms can inform future therapeutic strategies.
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