TY - JOUR
T1 - The epigenetic and transcriptional landscape of neuroendocrine prostate cancer
AU - Davies, Alastair
AU - Zoubeidi, Amina
AU - Selth, Luke A.
PY - 2020/2
Y1 - 2020/2
N2 - 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.
AB - 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.
KW - Androgen receptor
KW - DNA methylation
KW - Epigenetics
KW - Lineage plasticity
KW - Prostate cancer
KW - Transcription factor
UR - http://www.scopus.com/inward/record.url?scp=85077913826&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/1121057
U2 - 10.1530/ERC-19-0420
DO - 10.1530/ERC-19-0420
M3 - Review article
C2 - 31804971
AN - SCOPUS:85077913826
SN - 1351-0088
VL - 27
SP - R35-R50
JO - Endocrine-Related Cancer
JF - Endocrine-Related Cancer
IS - 2
ER -