Page 67 - Read Online

Page 272 de Kouchkovsky et al. J Transl Genet Genom 2021;5:265-77 https://dx.doi.org/10.20517/jtgg.2021.32

Table 3. Summary of key epigenetic mechanisms and pathways associated with t-SCNC
Gene/epigenetic Summary of findings Comments
mechanism
DNA methylation CpG methylation status shows a high degree of concordance between DNA methylation and gene expression levels Bisulfite sequencing of cell-free DNA is capable of distinguishing t-
across t-SCNC and mCRPC-adenocarcinoma samples [3,56] SCNC cases from mCRPC-adenocarcinoma and may provide a novel
[29]
non-invasive biomarker of t-SCNC
Histone acetylation t-SCNC is associated with increased histone acetylation of regulatory elements near neuronal and stemness genes, Increased rate of glycolysis in t-SCNC results in increased generation
[47] [58,59]
such as CHGA, ASCL1, and SOX2 of acetyl-CoA, a key substrate for histone acetylation
[3,61,62]
EZH2 The EZH2 histone methyltransferase is one of the topmost overexpressed epigenetic regulators in t-SCNC . Androgen deprivation increases EZH2 activity through PKA/CREB
EZH2 cooperates with N-MYC to downregulate AR target gene expression and promote neuronal transcriptional signaling [64] , offering a potential link between prolonged
programs [41,42,56] antiandrogen therapy and lineage plasticity
SRRM4 SRRM4 is upregulated in t-SCNC and accounts for the majority of alternative mRNA splicing events associated with SRRM4 has also been shown to induce a splice variant of the histone
[65]
t-SCNC . In particular, SRRM4 induces an inactive splice variant of REST-1 (a negative master regulator of modulator LSD1 (LSD1+8a), which in turn regulates AR signaling and
neuroendocrine differentiation), which is downregulated in up to 50% of t-SCNC tumors [67] promotes neuronal gene expression [73]
t-SCNC: Treatment-associated small cell neuroendocrine prostate cancer; mCRPC: metastatic castration-resistant prostate cancer; EZH2: enhancer of zeste homolog 2; AR: androgen receptor; LSD1: lysine-specific
demethylase 1; SRRM4: serine/arginine-repetitive matrix 4.

[64]
PKA/CREB signaling , suggesting a potential mechanism by which prolonged antiandrogen therapy may promote lineage plasticity. EZH2 has, in turn, been
shown to cooperate with N-MYC to downregulate AR target gene expression and promote neuronal transcriptional programs [41,42,56] . Conversely, EZH2
silencing in patient-derived t-SCNC models prevents neuroendocrine differentiation and leads to a decrease in global H3K27 methylation status associated
with downregulation of stemness and neuronal transcriptional programs [62,63] .

The serine/arginine-repetitive matrix 4 (SRRM4) splicing factor is also upregulated in t-SCNC and is estimated to account for the majority of alternative
[65]
[65]
splicing events associated with t-SCNC . Pre-clinical models suggest that its activity is enhanced by RB1/TP53 depletion and antiandrogen therapy . Genes
susceptible to SRRM4-mediated alternative splicing include a variety of other RNA splicing factors and neural-specific histone modifiers such as BHC80 and
LSD1, further highlighting the role of epigenetic reprogramming driving lineage plasticity and neuroendocrine differentiation. SRRM4 has also been shown to
induce an inactive splice variant of the repressor element-1 silencing transcription factor (REST-1). REST-1 is a negative master regulator of neuroendocrine
differentiation, and in its intact form, functions to suppress neuronal transcriptional programs in non-neuronal cells. It is also an important repressor of gene
expression in hypoxic conditions . Downregulation of REST is seen in up to 50% of t-SCNC tumors (compared with only 3% of metastatic prostate
[66]
adenocarcinoma) and has been shown to promote epithelial-mesenchymal transition and stemness transcriptional programs (e.g., SOX2, POU3F2) [32,68] .
[67]

[11]
Although AR independence is considered a hallmark of t-SCNC, persistent AR expression can still be seen in a subset of cases . Recent insights suggest a role
for epigenetic reprogramming of AR signaling in t-SCNC. Unlike pioneering transcription factors (such as FOXA1), which are able to bind to DNA within
areas of condensed chromatin, AR preferentially binds to open chromatin within nucleosome-depleted regions . Epigenetic mechanisms of chromatin
[69]