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Page 415 Lv. J Transl Genet Genom 2021;5:414-22 https://dx.doi.org/10.20517/jtgg.2021.34

INTRODUCTION
Prostate cancer (PCa) is one of the most frequent human malignancies and is the second leading cause of
[1]
death by cancer in the western male population . Currently, prostate-specific antigen (PSA) is a significant
marker for diagnosing PCa. Nevertheless, the accuracy and specificity of PSA for predicting PCa are not
[2]
high enough . Therefore, it is urgent to identify more effective diagnostic hallmarks and therapeutic targets
for PCa.

The high mobility group box 1 (HMGB1) protein is a ubiquitous non-histone component of chromatin that
[3-6]
is involved in DNA replication and DNA repair process . It has two main functions depending on the
cellular localization, post-translational modification. and context of the cell. In the cell nucleus, HMGB1
functions as a DNA-binding complex to sustain nucleosome structure without sequence specificity and aids
in distorting the DNA structure to allow access for repair and transcription proteins . The interactions of
[7,8]
HMGB1 with various transcription factors, such as NF-kB members , p53 , and TATA-binding
[10]
[9]
protein , can promote or suppress transcription depending on the cellular context. Owing to its ability to
[11]
bind distorted/damaged DNA structures, HMGB1 has been reported to be involved in four DNA repair
pathways: nucleotide excision repair, base excision repair, mismatch repair, and DNA double-strand break
repair .
[12]
Interestingly, HMGB1 not only promotes DNA damage recognition but can also increase DNA repair
efficiency through direct interactions with DNA repair enzymes . Besides, HMGB1 can also be subjected
[13]
to posttranslational modification, which modulates interactions of the proteins with DNA/chromatin and
regulates their nuclear translocation and secretion [6,14] . Accumulating evidence indicates that the role of
HMGB1 extends beyond the nucleus, notably its extracellular role in inflammation . Outside the cell, it
[15]
can be passively secreted from dying or stressed cells or actively secreted from immune cells, such as
activated macrophages, which can function as a danger signal and proinflammatory mediator through
interaction with multiple other molecules, including RNA, proteins, lipopolysaccharides, nucleosomes, and
several cell surface receptors [e.g., receptor for advanced glycation end product (RAGE), toll-like receptor
(TLR) 2, and TLR 4], with RAGE being regarded as a dominant receptor for HMGB1 in tumorigenesis [5,16] .
Extracellular HMGB1/RAGE interactions facilitate tumor proliferation via activation of p44/p42, p38, and
SAPK/JNK MAPKs . Moreover, HMGB1 also acts as a DNA-binding cytokine, which can activate
[17]
downstream immune responses or facilitate tumorigenesis by inducing inflammation [4,18-20] . For example, it
has been reported that enzalutamide-induced HMGB1 expression facilitates tumor-associated macrophage
recruitment and polarization and drives neuroendocrine differentiation via β-catenin stabilization,
indicating that HMGB1 may serve as a new treatment for enzalutamide resistance in patients with advanced
[21]
or metastatic PCa .
There is evidence that the HMGB1/RAGE axis is involved in inflammation-induced carcinogenesis .
[22]
RAGE, which belongs to the immunoglobulin superfamily, is a cell surface molecule and multi-ligand trans-
membranous receptor . HMGB1 is one of its ligand, and it has been reported to bind RAGE and
[23]
subsequently activate the mitogen-activated protein kinases in a variety of malignancies, such as colorectal,
pancreatic, breast, and oral squamous cell cancer [24-28] . Recent publications show that targeting RAGE
reduced the level of PSA, the downstream target gene of androgen receptor (AR) , indicating that RAGE
[29]
[30]
may play a pivotal role in the regulation of AR in PCa cells. Furthermore, Zhou et al. reported that the
HMGB1/TLR4-RAGE/sCLU pathway leads to chemoresistance in human prostate tumor cells by triggering
the process of cell death, thus providing a survival advantage to residual viable tumor cells.