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de Kouchkovsky et al. J Transl Genet Genom 2021;5:265-77 https://dx.doi.org/10.20517/jtgg.2021.32 Page 271

Table 2. Summary of key transcriptional programs associated with t-SCNC
Gene/pathway Summary of findings Comments
SOX2 The “stemness” transcriptional factor SOX2 is a key mediator of lineage plasticity in RB1/TP53 depleted SOX2 transcriptional regulation does not appear to be mediated by direct DNA binding
[23]
prostate cancer . SOX2 upregulation promotes the expression of pluripotency genes and represses but rather through modulation of histone H3 methylation status and chromatin
[40] [40]
master regulators of adenocarcinoma-lineage such as FOXA1 accessibility
MYCN MYCN expression is upregulated in t-SCNC samples relative to localized prostate adenocarcinoma and Androgen depletion induces a shift in the N-MYC cistrome towards neural development
[42] [42]
mCRPC . N-MYC cooperates with EZH2 to downregulate AR transcriptional programs and promotes and lineage pathways genes , thus providing a potential link between exposure to
resistance to AR-targeted therapy androgen deprivation therapy and the emergence of t-SCNC
FOXA1 FOXA1 is a pioneer transcription factor, which maintains epithelial differentiation in prostate and Mutations in the R219 hotspot of the FOXA1 forkhead domain are associated with t-SCNC
prostate cancer cells. FOXA1 gene expression is significantly lower among t-SCNC samples when and result in non-canonical FOXA1 signaling and activation of mesenchymal and
[46] [30]
compared to prostatic adenocarcinoma neuroendocrine transcriptional programs
FOXA2 FOXA2 is a topmost master regulator of neuroendocrine differentiation, upregulated in up to75% of t- FOXA2 upregulation is mediated by the removal of repressive histone methylation marks
[14,51] [52]
SCNC cases staining (vs. only 4% of mCRPC-adenocarcinoma samples) in the FOXA2 promoter region
ONECUT2 Several analyses have identified ONECUT2 as a key master regulator of t-SCNC through the promotion ONECUT2 has also been implicated in hypoxia-induced neuroendocrine differentiation
[55]
of neuronal, stem-cell, and cell cycle-related transcriptional programs and downregulation of AR and through SMAD3 signaling
[54,55]
FOXA1 activity
t-SCNC: Treatment-associated small cell neuroendocrine prostate cancer; mCRPC: metastatic castration-resistant prostate cancer; EZH2: enhancer of zeste homolog 2; AR: androgen receptor.
[47]
been associated with nearby regions of increased histone acetylation . Importantly, these dramatic shifts in the epigenetic landscape of t-SCNC are supported
by significant changes in tumor metabolism: increased glycolysis - and the resulting production of acetyl-CoA from pyruvate - provides a key substrate for
histone acetylation [58,59] . Decreased expression of protein kinase C λ/ι and upregulation of phosphoglycerate dehydrogenase (PHDGH) in t-SCNC leads to
[60]
increased S-adenosyl methionine (SAM) synthesis, which in turn provides methyl groups required for DNA and histone methylation . Interestingly,
treatment of PC cells with cycloleucine (an inhibitor of SAM synthesis) has been shown to reduced neuroendocrine and basal markers . The interplay
[60]
between tumor metabolism and epigenetic mechanisms suggests a potential for metabolic-directed therapies to reverse lineage plasticity and restore AR-
dependence in t-SCNC.

In addition to these genome-wide differences, several specific epigenetic pathways and regulators have been implicated in the emergence of t-SCNC [Table 3].
The histone methylase polycomb repressive complex 2 (PRC2) is a key epigenetic regulator of transcription, repressing gene expression through methylation of
histone 3 lysine 27 (H3K27me3) on nucleosomes. The histone-lysine N-methyltransferase Enhancer of zeste homolog 2 (EZH2) constitutes the major catalytic
enzyme of PRC2 and has emerged in recent years as one of the most important drivers of epigenetic reprogramming in t-SCNC. Indeed, transcriptional
profiling of various t-SCNC samples and pre-clinical models have consistently identified EZH2 as one of the topmost overexpressed epigenetic regulators in t-
SCNC [3,61,62] . Furthermore, EZH2 silencing has been shown to prevent neuroendocrine differentiation in several patient-derived xenografts and organoid
models of t-SCNC [62,63] . However, the exact mechanism through which EZH2 contributes to the development of t-SCNC has not been fully elucidated. EZH2 is
a transcriptional target of E2F1 and is upregulated in RB1 depleted tumors [24,62] . Androgen deprivation has also been shown to increase EZH2 activity through