Cervical cancer (CC) is the fourth most frequently
diagnosed cancer among women worldwide, accounting for ~266,000
deaths and 528,000 new cases each year (1). CC contributes to 7.5% of all female
cancer-related deaths, establishing itself as a notable cause of
mortality among women (2).
Well-structured screening programs that incorporate affordable
treatment techniques, such as cryotherapy, loop electrosurgical
excision and thermal ablation, can facilitate the early detection
and management of precancerous lesions, thereby reducing the
overall disease burden (3).
Nevertheless, in low- and middle-income countries,
late-stage CC remains prevalent due to limited access to early
diagnostic services and preventive care. Although chemotherapy and
radiotherapy continue to serve as the standard treatments for CC,
their overall effectiveness remains limited, with a number of
patients exhibiting suboptimal responses (4). Notably, targeted therapy and
immunotherapy have gained recognition as promising treatment
strategies. The approval of PD-1 inhibitors for the management of
recurrent or metastatic CC has enhanced host immune responses
against human papillomavirus (HPV)-positive malignancies (5). However, despite their potential,
several challenges persist, including the immunosuppressive tumor
microenvironment, tumor immune evasion, low patient response rates
and acquired drug resistance, all of which compromise treatment
(6). In the future, treatment
paradigms are expected to emphasize personalized medicine by
refining targeted therapies to improve cure rates and extend
patient survival.
Eukaryotic chromatin is primarily composed of
histones and nucleosomes, with nucleosomes consisting of DNA
wrapped around histone proteins. The tail regions of histones
frequently undergo a range of post-translational modifications
(7), collectively referred to as
histone modifications. These modifications influence gene
transcription through multiple pathways (8) and are essential for several key
biological processes. Common histone modifications include
acetylation, methylation and ubiquitination, with acetylation and
methylation recognized as the predominant types (9). Recently, additional modifications,
such as glycosylation, lactylation and palmitoylation, have been
identified, further increasing the complexity of histone regulation
(10–13). These modifications are vital for
regulating gene expression, repairing DNA damage, and controlling
the cell cycle, differentiation, apoptosis and tumor progression
(14,15).
Histone modifications may act cooperatively or
antagonistically, contributing to the formation of a ‘histone code’
that fine-tunes cellular functions (16,17).
Disruptions in histone modification patterns are closely associated
with various diseases, including cancer, neurodegenerative
disorders and immune dysfunction, in which these alterations in
gene expression contribute to disease progression (18,19).
As a result, epigenetic therapies targeting histone modifications
have emerged as a critical area of research in precision
medicine.
In CC, histone modifications, an essential component
of epigenetic regulation, affect key processes such as persistent
HPV infection, dysregulation of the cell cycle, immune evasion and
treatment resistance. These pathological features arise from
chromatin remodeling and aberrant gene expression (20). Epigenetic therapies aimed at
correcting abnormal histone modifications, including histone
deacetylase (HDAC) inhibitors, are increasingly being recognized as
potential treatments for CC (20).
Therefore, a comprehensive analysis of the role of histone
modifications in CC and their clinical implications may offer
valuable insights into precision treatment strategies.
CC ranks as the fourth most frequently diagnosed
cancer among women worldwide, with ~660,000 new cases reported in
2022 (21). The World Health
Organization estimates that CC affects 662,000 individuals
globally, including 151,000 women in China (22). Despite a substantial reduction in
incidence over the past three decades, CC remains a major global
public health concern, with considerable regional disparities in
both incidence and mortality rates (23,24).
In high-income countries, incidence and mortality rates are notably
lower than those in developing regions, largely due to widespread
HPV vaccination, comprehensive screening programs and greater
access to healthcare resources (25–27).
Nevertheless, in the later stages of CC, mortality rates in
developed nations can be elevated or comparable to those in
developing countries, primarily due to the limited availability of
effective treatments for advanced disease (28).
CC can be classified into two primary histological
types: Cervical squamous cell carcinoma (CSCC), which arises from
squamous cells; and cervical adenocarcinoma, which originates from
glandular epithelial cells (29).
CSCC accounts for >80% of CC cases worldwide and is associated
with high incidence and mortality rates (25). This cancer progresses through a
series of well-defined precancerous stages, culminating in cellular
dysplasia, cervical intraepithelial neoplasia, and ultimately,
squamous cell carcinoma (30).
All HPV types, regardless of risk classification,
infect epithelial cells, particularly keratinocytes, leading to
cellular immortalization (30). The
HPV genome consists of three primary functional regions: The early
(E) region, which encodes proteins E1-E7 that are necessary for
viral replication; the late (L) region, which produces structural
proteins L1 and L2 that are essential for virion assembly; and the
long control region, a non-coding segment that contains
cis-regulatory elements critical for DNA replication and
transcription (33). E1 and E2 are
essential for viral DNA replication and act as transcriptional
regulators. The viral genome also encodes early genes, such as E5,
E6 and E7, which contribute to oncogenic transformation. E5
enhances immune evasion, reduces dependence on growth factors and
promotes cellular proliferation (34). E6 interacts with the tumor
suppressor protein p53, leading to its degradation (35). E7 binds to retinoblastoma protein,
mediating its degradation via the ubiquitin-proteasome system and
promoting cell cycle progression (36).
During the later phases of infection, viral late
genes become active within the suprabasal layers, initiating
circular genome replication and the synthesis of structural
proteins. As the virus ascends to the outer layers of the skin or
mucosal surfaces, mature viral particles are assembled and
subsequently released. Additionally, HPV alters gene expression and
activates several signaling pathways, such as those mediated by
growth factor receptors, Notch, RAS and PI3K/Akt/mTOR, all of which
promote host cell survival and proliferation. These molecular
alterations collectively contribute to cervical carcinogenesis
(37–39) (Fig.
1).
Given the pivotal role of HPV in the pathogenesis of
CC, prevention strategies targeting the virus have proven highly
effective. Specifically, vaccination against high-risk HPV types
has led to a notable reduction in CC incidence, particularly in
developed countries (40). In
addition, surgery, radiotherapy and chemotherapy are the standard
treatments for locally advanced cervical cancer and have notably
reduced the mortality rate of patients with CC; however, their
effectiveness in treating more advanced or recurrent disease
remains limited (41–43).
Advancements in immunotherapy and targeted therapy
have demonstrated considerable promise in cancer treatment.
Inhibitors of PD-1/PD-L1, such as nivolumab and pembrolizumab,
function by disrupting immune checkpoint pathways, thereby
enhancing the ability of the immune system to detect and eliminate
cancer cells (44). Additionally,
the use of CTLA-4 inhibitors, such as ipilimumab, has been explored
as an immune checkpoint-based therapy for CC (45). Emerging evidence has indicated that
these therapies exhibit substantial efficacy, particularly when
combined with chemotherapy or radiotherapy, in patients with
advanced or recurrent disease (46,47).
Although these therapies hold considerable promise,
several challenges persist. Immunotherapy can induce immune-related
adverse events, such as autoimmune disorders and severe
inflammation, and its efficacy is often reduced in tumors
exhibiting strong immune tolerance (48–50).
Similarly, although targeted therapies are designed to act on
specific molecular targets, their effectiveness is limited by tumor
heterogeneity and the development of drug resistance, thereby
reducing their long-term efficacy (48–50).
Moreover, the success of both therapeutic approaches is influenced
by individual patient factors and the complexity of the tumor
microenvironment (48–50). As a result, future therapeutic
strategies should emphasize personalized medicine and the continued
development of targeted therapies, with the aim of improving cure
rates and extending patient survival.
Histone modifications serve a critical role in
regulating biological processes by altering chromatin structure,
thereby influencing the expression of specific genes. Although most
research has focused on well-characterized modifications, such as
acetylation, methylation and phosphorylation, histones also undergo
a variety of other modifications (51). These include citrullination,
ubiquitination, ADP-ribosylation and O-GlcNAcylation, as well as
less-studied modifications such as propionylation, butyrylation,
crotonylation, lactylation and palmitoylation (51). These diverse modifications affect
chromatin structure and gene expression, contributing to critical
processes such as the cell cycle, DNA repair, differentiation and
immune regulation. They also serve a role in the pathogenesis of
diseases, including cancer (including CC), neurodegenerative
disorders (such as Alzheimer's disease) and metabolic conditions
(including diabetes mellitus) (52–54).
The regulation of histone modifications is mediated
by ‘writers’ and ‘erasers’, enzymes that add or remove
modifications, thereby ensuring appropriate gene expression
(55). For example, histone
acetyltransferases (HATs) introduce acetyl groups, leading to
chromatin relaxation and enhanced transcription, whereas HDACs
remove acetyl groups, resulting in chromatin condensation and
transcriptional repression (56).
Similarly, histone methylation is catalyzed by histone
methyltransferases (HMTs), whereas histone demethylases are
responsible for removing methyl groups. The coordinated activity of
these enzymes modulates chromatin architecture and is essential for
the regulation of gene expression (57). Notably, certain ‘writers’ and
‘erasers’ are capable of regulating multiple types of histone
modifications. For example, G9a, a HMT, primarily catalyzes the
methylation of lysine 9 on histone H3 (H3K9), but also modulates
histone acetylation, thereby influencing gene silencing and
chromatin structure (58).
Likewise, p300/CBP, a HAT, facilitates histone acetylation and
transcriptional activation (59),
and has also been shown to catalyze histone lactylation, a
modification particularly relevant under conditions of altered
cellular metabolism, such as hypoxia or inflammation (60). Similarly, HDACs primarily remove
acetyl groups, leading to chromatin condensation and
transcriptional repression; however, certain HDAC family members,
such as sirtuin (SIRT)1, serve pivotal roles not only in histone
deacetylation but also in regulating non-histone proteins, such as
p53, thereby modulating apoptosis and DNA repair (61,62).
In addition, lysine-specific demethylase (KDM)1, an ‘eraser’, can
remove methyl groups from lysine 4 on histone H3 (H3K4) to suppress
gene expression and from H3K9 to promote gene activation (54,63).
The cross-regulation by these multifunctional enzymes indicates
that histone modification is not a linear process but rather a
highly dynamic and interactive network that enables precise control
of gene expression, allowing cells to adapt to environmental
changes and maintain gene expression homeostasis. A comprehensive
summary of the major histone modifications, including ‘writer’ and
‘eraser’ proteins, their family classifications, target sites and
functional roles, is presented in Table
I.
Histone modifications are fundamental to the
initiation and progression of cancer, primarily through their
effects on chromatin structure and gene expression. Consequently,
these modifications influence the transcription of genes involved
in tumorigenesis. Aberrant histone modifications, including
acetylation, methylation, phosphorylation and ubiquitination, can
lead to the silencing of tumor suppressor genes or the activation
of oncogenes, thereby facilitating tumor progression. For example,
trimethylation of lysine 27 on histone H3 (H3K27me3), a repressive
histone mark mediated by EZH2, is frequently observed in breast
cancer and hepatocellular carcinoma (HCC), leading to the silencing
of key tumor suppressor genes (64,65).
For example, EZH2 promotes the stemness of HCC by inducing the
transcriptional repression of the tumor suppressor gene TOP2A
through H3K27me3-mediated silencing (65). Similarly, elevated levels of histone
H3 lysine 9 acetylation (H3K9ac) and H3 lysine 27 acetylation have
been associated with oncogene activation, contributing to the
progression of colorectal and lung cancer (66). Moreover, histone modifications
influence DNA damage repair pathways; for example, phosphorylation
of H2AX is activated in response to DNA damage, and affect the
tumor microenvironment, such as HDAC-driven immune suppression
(67). They are also associated
with resistance mechanisms; for example, KDM5A-mediated
demethylation enhances chemotherapy resistance (68). As a result, epigenetic therapies
targeting histone modifications, including inhibitors of HDACs and
HMTs/KDMs, hold notable promise for precision cancer treatment,
particularly when used in combination with immunotherapy and
molecular targeted therapies.
Histone modifications serve a critical role in
regulating the initiation, progression and therapeutic response of
CC. Modifications such as acetylation, methylation, phosphorylation
and ubiquitination are central to modulating gene expression,
altering chromatin architecture and influencing cellular signaling
networks, all of which contribute to cancer development. Aberrant
histone modifications can lead to the suppression of tumor
suppressor genes or the activation of oncogenes, thereby promoting
cellular processes, such as proliferation, invasion and immune
evasion. Furthermore, histone modifications are closely associated
with the development of resistance to therapies, including
chemotherapy, radiotherapy and targeted treatments. This section
examines the role of histone modifications in the pathophysiology
of CC.
Histone acetylation, regulated by HATs and HDACs, is
a reversible and dynamic process. HATs modify nucleosome structure
by promoting chromatin relaxation, thereby facilitating gene
transcription (Fig. 2). More than
20 HAT proteins have been identified, with key members belonging to
the GNAT, MYST and p300/CBP families (69). Yang et al (70) demonstrated that the HAT CSRP2BP
markedly promotes epithelial-mesenchymal transition (EMT) and
metastasis in CC cells by activating N-cadherin. Notably, in CC
tissues, elevated CSRP2BP expression was observed and revealed to
be associated with poor prognosis. Furthermore, overexpression of
CSRP2BP enhanced the proliferation and metastasis of CC cells in
both in vitro and in vivo models, whereas its
silencing had the opposite effect. CSRP2BP was also identified as a
key contributor to cisplatin resistance. At the molecular level,
CSRP2BP was revealed to catalyze acetylation of histone H4 at
lysine residues 5 and 12, to form a complex with the transcription
factor SMAD4 and to bind to the SEB2 sequence in the promoter
region of N-cadherin, thereby upregulating its transcription. This
mechanism may promote EMT and enhance metastasis in CC cells
(70). These findings underscore
the essential role of histone acetylation in the initiation,
progression and development of drug resistance in CC. Similarly,
the acetyltransferase p300 catalyzes acetylation of histone H3 at
lysine 27 (H3K27), which enhances the activity of the NDUFA8
promoter, thereby stimulating CC cell proliferation (71).
Histone methylation is a dynamic and reversible
process regulated by HMTs and KDMs. Methylation occurs through the
activity of HMTs, which add methyl groups to specific histone
residues, thereby modifying chromatin structure and function. These
modifications are typically associated with either gene activation
or repression, depending on the specific site and context (88–90).
Numerous HMTs, including members of the SET, DOT1L and SUV39H
families, are involved in regulating gene expression, DNA repair
mechanisms and cell cycle progression (88–90).
Zhang et al (91)
demonstrated that HPV18 E6/E7 increases the transcriptional
activity of EZH2, resulting in elevated H3K27me3 levels in CC.
Furthermore, Beyer et al showed that histone modifications,
such as H3K9ac and trimethylation of lysine 4 on histone H3 are
closely associated with clinicopathological parameters and 10-year
survival outcomes, underscoring their prognostic value in CC
(92). Chen et al (93) reported that NSD2, a HMT, promotes
proliferation, migration and invasion of CC cells by activating the
endothelial nitric oxide synthase and AKT/MMP-2 signaling pathways.
Additionally, Ansari et al (94) identified the H3K4-specific
methyltransferase MLL as a critical factor in cervical tumor
growth. Knockdown of MLL reduced the expression of several key
growth and angiogenesis-related factors, including HIF1α, VEGF and
CD31, thereby inhibiting CC progression. Notably, studies have
shown interest in histone methylation enzymes as potential
therapeutic targets. Zhang et al (95) reported that SUV39H1 upregulates
DNMT3A expression in CC cells via trimethylation of lysine 9 on
histone H3, while simultaneously downregulating immunosuppressive
factors. such as Tim-3 and galectin-9. This activity may improve
the tumor immune microenvironment and enhance therapeutic efficacy.
Moreover, Osawa et al (96)
showed that the histone demethylase JHDM1D suppresses
angiogenesis-related factors, including VEGF-B and angiopoietin,
under conditions of nutrient deprivation, thereby limiting
angiogenesis and exerting tumor-suppressive effects.
In summary, studies have identified the critical
roles of histone methylation and demethylation in tumor
progression, immune regulation, cell invasion and angiogenesis, all
of which markedly contribute to CC development.
The regulation of histone phosphorylation involves
histone kinases (HKs) and phosphatases (PPs), with both enzymatic
processes being dynamic and reversible. Histone phosphorylation,
catalyzed by HKs, modifies chromatin structure and function,
typically influencing gene transcription by either activating or
repressing it (97,98). Several HKs, including members of the
Aurora, CDK and MSK families, serve essential roles in gene
expression, DNA repair, cell cycle progression and signal
transduction (97,98). In CC cells, phosphorylation of
histone H2AX serves as a key indicator of DNA damage, reflecting
cellular sensitivity to radiation and the efficiency of DNA repair
mechanisms; this makes H2AX phosphorylation a promising biomarker
for evaluating the therapeutic response to radiotherapy in CC
(99). Zhao et al (100) also reported that alterations in
H2AX phosphorylation levels before and after neoadjuvant
chemotherapy provide valuable insights for assessing treatment
response in patients with CC. Several additional studies have
investigated histone phosphorylation as a potential biomarker for
prognosis and treatment efficacy in CC (101–103).
Preclinical studies have further suggested that
targeting PPs or their upstream kinases can effectively inhibit
tumor growth. For example, Zhang and Zhang (104) demonstrated that ZM447439, a potent
Aurora kinase B inhibitor, suppresses the proliferation of SiHa CC
cells while enhancing cisplatin sensitivity. Similarly, Cheung
et al (105) reported that
BPR1K653, a novel Aurora kinase inhibitor, exhibits strong
antiproliferative effects in multidrug-resistant cancer cells
mediated by MDR1 (P-gp170).
In conclusion, although histone phosphorylation has
been extensively studied in various tumors, research specifically
focusing on CC remains limited. Most studies have investigated
phosphorylated histones as potential biomarkers or examined HKs
that suppress CC progression. However, these investigations are
still relatively preliminary and lack comprehensive mechanistic
insights.
Histone lactylation is a newly identified epigenetic
modification in which lactate molecules are covalently attached to
lysine residues on histones, resulting in altered chromatin
structure and changes in gene transcription. This modification has
attracted increasing scientific attention over the past 3 years
(106). In CC, a previous study
has shown that DPF2, a member of the DPF protein family, recognizes
lactylated histones and facilitates gene activation. Specifically,
DPF2 binds to lactylated histones and promotes the transcription of
target genes (SEMA5A, FUT8, ROCK1 and SOAT1), thereby contributing
to the initiation and progression of CC. Histone lactylation is
closely associated with cellular metabolism and transcriptional
regulation, and serves a substantial role in CC development. These
findings suggest that DPF2 may serve as a promising therapeutic
target for CC (106). In addition,
histone lactylation presents potential therapeutic targets for
metabolic and immune-based interventions. Huang et al
(107) investigated how CC cells
modulate histone lactylation in macrophages through lactate
secretion. Their findings revealed that lactate released by CC
cells upregulates lactylation of lysine 18 on histone and M2
macrophage markers (arginase-1), while downregulating M1 markers
(inducible nitric oxide synthase). Overall, lactate was shown to
enhance GPD2 expression via histone lactylation, promoting M2
macrophage polarization and facilitating tumor progression. In
summary, although histone lactylation is a relatively recent
discovery with limited research in CC, its critical role in other
malignancies underscores the importance of further investigation
(Fig. 3).
Crotonylation is a histone modification in which a
crotonyl group, an unsaturated short-chain fatty acid, is added to
lysine residues on histones. This modification is associated with
gene activation and the regulation of cellular metabolism. Over the
past 3 years, crotonylation has garnered increasing attention in
epigenetics research (108). In
CC, a previous study has shown that p300-mediated crotonylation
enhances the proliferation, invasion and migration of HeLa cells by
promoting the activity of heterogeneous nuclear ribonucleoprotein
A1 (hnRNP A1). Specifically, p300 modulates hnRNP A1 function by
catalyzing histone crotonylation, which subsequently influences
transcriptional and epigenetic regulation. This pathway serves a
critical role in tumor growth and metastasis (108).
Several other histone modifications, such as
ubiquitination, ADP-ribosylation, palmitoylation, propionylation
and butyrylation, remain either rare or relatively newly
characterized, thereby limiting their current investigation in CC.
However, these modifications are expected to become important areas
of future research, offering considerable potential for
understanding the epigenetic regulation of CC.
Numerous preclinical studies have explored the
potential of targeting histone-modifying enzymes as a therapeutic
approach for CC. Histone modifications, such as acetylation and
methylation, serve essential roles in regulating cancer cell
proliferation, metastasis and resistance to therapy. For example,
small-molecule inhibitors (such as p-coumaric acid, ferulic acid,
sinapinic acid and resveratrol) that target HDACs or HMTs have
demonstrated efficacy in reducing the proliferation and migration
of CC cells, thereby inhibiting tumor progression (109–112).
In addition, some clinical studies have begun
investigating the utility of histone modifications as prognostic
biomarkers (97,103). By examining specific histone
modification patterns in CC tissues, clinicians can obtain early
insights into disease progression, recurrence risk and treatment
response. Changes in histone modifications may be associated with
tumor invasiveness, metastatic potential and resistance to standard
therapies, offering valuable guidance for personalized treatment
planning.
Although the clinical application of histone
modification-targeted therapies in CC is still in its infancy, such
agents, especially in the context of hematologic malignancies, have
already advanced to large-scale clinical trials and have
demonstrated encouraging results (Table II). Ongoing research suggests that
these strategies may evolve into effective therapeutic options for
CC. In the future, precise modulation of histone modification
pathways could lead to advancements in early detection, prognostic
evaluation and the development of individualized treatment
strategies.
Histone modifications serve a crucial role in
regulating the proliferation, migration, invasion and drug
resistance of CC cells by altering chromatin structure and
modulating gene expression. Although research into therapies
targeting histone modifications in CC is still in its early stages,
preclinical studies have suggested that enzymes such as HDACs and
HMTs may effectively inhibit tumor growth and metastasis.
Moreover, histone modifications hold promise as
biomarkers for early diagnosis, prognostic assessment and
monitoring therapeutic responses. Distinct histone modification
patterns may help predict tumor invasiveness and response to
treatment. While drugs targeting histone modifications have not yet
undergone widespread clinical testing in CC, emerging research
indicates that these therapies may represent a novel option for
personalized treatment strategies.
However, in low- and middle-income countries, the
high cost and limited accessibility of histone
modification-targeting therapies present substantial barriers to
their use. Challenges such as inadequate healthcare infrastructure,
unstable drug supply chains and restricted insurance coverage
prevent a number of patients from receiving timely and effective
treatments (113–115). Therefore, reducing drug costs,
enhancing access to therapies and strengthening public health
policy support are critical steps toward expanding the availability
of these promising treatments, particularly for CC, which has a
disproportionately high incidence in resource-limited settings.
In conclusion, histone modifications are integral to
the pathogenesis of CC and offer substantial clinical potential.
Future research should focus on elucidating the molecular
mechanisms underlying these modifications and advancing clinically
applicable therapies for early detection, individualized treatment
and prognostic prediction.
Not applicable.
Funding: No funding was received.
Not applicable.
All authors contributed to the conception and design
of the study. XL, MZ and ZR drafted the initial manuscript and
prepared the figures. JY and SY provided constructive feedback.
Data authentication is not applicable. All authors read and
approved the final version of the manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
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