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Page 350 Jones et al. J Transl Genet Genom 2021;5:341-56 https://dx.doi.org/10.20517/jtgg.2021.19

or DNA binding proteins to access DNA and control gene expression. This section will focus on chromatin
remodeling as a compelling target for PCa therapeutic approaches.

ASF1A
Anti-silencing function 1A histone chaperone (ASF1A) is a major isoform of ASF1, a small histone
chaperone of the H3/H4 family and conserved from yeast and human cells . As the major isoform of
[105]
[106]
ASF1 in human cells, ASF1A is ubiquitously expressed in all tissues and throughout the cell cycle . The
elevated expression of ASF1A positively correlates with the level of H3K56Ac , which is a mark of newly
[107]
replicated chromatin as well as replication-independent histone replacement. ASF1A contributes to the
resistance of DNA damage tolerance because of its ability to promote double-strand break (DSB) repair by
non-homologous end joining. ASF1A deficiency and loss will render cells more sensitive to DSBs. For
example, knockout ASF1A leads to the introduction of DSBs, which sensitizes cancer cells to radiotherapy,
chemotherapy, and immunotherapy [108,109] . ASF1A has emerged as an oncogenic driver. Regarding several
cancer cases, ASF1A accumulation is a general characteristic that occurs in tumorigenesis . ASF1A is
[110]
highly expressed in prostate cancer cells, and its overexpression is associated with poor prognosis in cancer
patients [104,111-113] . Some reports have shown that blocking the expression of ASF1A by RNA
interference [108,111] , small inhibitors, and chemotherapy drugs can effectively inhibit the proliferation and
[110]
growth of tumors and improve the sensitivity to anti-cancer drugs and immunotherapy [108,109] .

CAF-1
Histone chaperone chromatin assembly factor-1 (CAF-1) is composed of p150 large unit (CHAF1A), p60
middle unit (CHAF1B), and p48 small unit (RbAp48) and is involved in the deposition of (H3-H4)
2
tetramer onto DNA . During replication, CAF-1 receives (H3-H4) tetramer from another histone
[114]
2
chaperone ASF1A and then deposits the histone onto the newly synthesized daughter DNA strands [114,115] . It
has been reported that the dysregulation of histone assembly is closely associated with certain human
[116]
[117]
diseases such as cancer . Indeed, CAF-1 has been shown to be a marker of proliferating cells , and
depletion of CAF-1 induces cell death, possibly due to the activation of DNA damage response pathway .
[118]
Specifically, in PCa, the middle unit of CAF-1 is a prognostic marker of adverse outcomes for patients ,
[111]
[119]
and inhibition of ASF1A suppresses the growth of PCa . These interesting results raise the possibility that
targeting chromatin assembly in PCa is a potential treatment for PCa patients.
SAFB1
SAFB1 (scaffold attachment factor B1) is a nonenzymatic architectural component of the chromatin that
was first identified to bind adenine- and thymine-rich scaffold/matrix attachment (S/MAR) regions to
[120]
divide the genome into 5-200 kb topological domains. SAFB1 was previously assumed to mediate chromatin
[119]
looping to modulate long-range chromatin interactions and higher-order chromatin structure . SAFB1 is
a component of the DNA damage response and cooperates with histone acetylation to allow for efficient
gH2AX spreading and genotoxic stress signaling. SAFB1 undergoes a highly dynamic exchange at damaged
chromatin in a poly (ADP-ribose)-polymerase 1- and poly (ADP-ribose)-dependent manner and is required
for unperturbed cell cycle checkpoint activation and guarding cells against replicative stress . Meanwhile,
[121]
SAFB1 regulates RNA polymerase II-dependent transcription of targeted genes . There is a potent
[119]
transcriptional repression domain at the C-terminal region of SAFB1, which mediates the transcriptional
repression activity. Particularly, SAFB1 binds to nuclear receptors [122,123] and suppresses immune regulators
and apoptotic genes . SAFB1 attenuates ERα transcriptional activity via its interaction with the ERα DNA-
[124]
[125]
binding domain in a ligand-independent manner . Low levels of SAFB1 were found to correlate with
[126]
worse outcomes in breast cancer patients . In addition, SAFB1 is also reduced with disease progression in
a cohort of human PCa, including metastatic tumors. SAFB1 binds to AR and is phosphorylated by the