Introduction
N6-methyladenosine (m6A) represents one of the most
prevalent chemical modifications in eukaryotic messenger RNA (mRNA)
and non-coding RNA, and it serves a key role in several aspects of
RNA metabolism (1), including
splicing, nuclear export, translation and degradation. This dynamic
and reversible modification is installed by methyltransferase
complexes, primarily composed of methyltransferase-like 3 (METTL3)
(2–4) and METTL14 (5–7), and
removed by demethylases such as Fat mass and obesity-associated
protein (FTO) (8–10) and AlkB homolog 5 (ALKBH5) (11–14).
Emerging evidence has highlighted the critical role of m6A
modifications in the pathogenesis and progression of various types
of cancer, including melanoma. Melanoma is a highly aggressive
malignancy with a persistently increasing global incidence
(15), while its development has
been strongly associated with dysregulation of m6A homeostasis
(16,17). These imbalances can affect the
expression and stability of oncogenes or tumor suppressors, thus
influencing tumor cell proliferation, migration and invasion.
Consequently, elucidating the mechanistic roles of m6A
modifications in melanoma is essential for uncovering the
underlying molecular mechanisms of this disease and identifying
novel diagnostic and therapeutic targets.
However, the regulatory network of m6A modification
in melanoma, a specific tumor type, remains unclear; in particular
how it integrates different signaling pathways to synergistically
regulate tumor invasion and metastasis, which are core malignant
phenotypes. The present review aimed to systematically summarize
the latest progress of m6A regulatory factors in melanoma invasion
and metastasis, focusing on the specific signaling axes mediated by
key molecules such as METTL3, ALKBH5 and FTO, and outlining a
clearer m6A regulatory network to provide a theoretical basis for a
deeper understanding of melanoma pathogenesis and the development
of new therapeutic strategies.
Epidemiological features and clinical impact
of melanoma
Melanoma is a highly malignant cutaneous neoplasm
with an increasing incidence worldwide. Epidemiological data
indicate that its risk rises with advancing age (18). Globally, ~232,100 new cases of
cutaneous melanoma are diagnosed annually, accounting for ~55,500
mortalities, or ~0.7% of all cancer-related mortality (15).
The clinical severity of melanoma stems primarily
from its aggressive biological behavior and metastatic potential.
While early-stage melanoma is commonly curable, metastatic disease
is associated with poor prognosis (19). The most common sites of metastasis
include lymph nodes, lungs, liver, and brain, and treatment
outcomes for disseminated disease are generally unfavorable
(20,21). The frequent lack of obvious symptoms
during the early stages of the disease can result in delayed
diagnosis or misdiagnosis, eventually leading to missed
opportunities for early intervention. Therefore, improving public
awareness, enhancing early prevention and implementing effective
screening programs are essential for mitigating disease burden and
improving survival outcomes.
Melanomagenesis and metastasis are driven by complex
molecular mechanisms, including mutations in BRAF (22), alterations in p53 (23) and CDKN2A (24), and dynamic changes in the tumor
microenvironment (25). Although
advances in immunotherapy and targeted therapy have markedly
improved patient outcomes, the management of advanced melanoma
remains a major clinical challenge.
Overview of m6A modification
m6A is the most abundant internal
post-transcriptional RNA modification. It is widely distributed
across mammals, plants and some prokaryotes, and serves a key role
in regulating RNA metabolism, including RNA transport, stability,
splicing, translation and RNA-protein interactions (26,27).
The presence of m6A in RNA was first reported in viral transcripts
(28). m6A methylation
predominantly occurs near stop codons and within 3′ untranslated
regions (3′-UTRs). The dynamic regulation of m6A is mediated by
three classes of regulatory factors: ‘Writers’
(methyltransferases), ‘erasers’ (demethylases) and ‘readers’
(m6A-binding proteins) (29).
Writers catalyze the deposition of m6A; reader proteins interpret
these modifications to determine RNA fate; and erasers remove these
modifications to maintain dynamic regulation. The METTL3-METTL14
complex serves as the core catalytic machinery for m6A
installation, while FTO and ALKBH5 function as the primary erasers
(30). Dysregulation of m6A
modification has been implicated in the pathogenesis of several
types of cancer, including leukemia, breast cancer and melanoma
(31,32). Due to its involvement in a wide
range of pathological conditions, including type 2 diabetes
(33), non-alcoholic fatty liver
disease (34), gastric cancer
(2) and bladder cancer (3), m6A methylation is increasingly
recognized as a promising biomarker for early diagnosis and
prognosis assessment in several diseases.
Regulators of m6A modification
m6A methyltransferases (writers)
METTL3 is the core catalytic component of the m6A
methyltransferase complex and is primarily responsible for
catalyzing m6A deposition on mRNA (35). Using S-adenosylmethionine as a
methyl donor, METTL3 methylates adenosine residues within the
consensus DRACH motif. METTL3 contains several functional domains,
including an N-terminal helix domain, a nuclear localization signal
domain and a zinc finger CCCH domain that promotes RNA binding and
methylation. METTL3 is essential for various physiological
processes, such as embryonic development, cellular reprogramming,
and maintenance of cellular homeostasis (36). This METTL3-METTL14 heterodimer forms
the core m6A methyltransferase complex (MAC) (37), which is further regulated by
additional regulatory subunits constituting the m6A-METTL
associated complex (38).
METTL14 is an essential, albeit non-catalytic,
structural component of the m6A methyltransferase complex that acts
in cooperation with METTL3 (39).
Structurally, the N-terminus of METTL14 interacts with METTL3
through loop and helical domains, while their respective C- and
N-terminal regions form parallel helices, which stabilize the
heterodimer and facilitate efficient m6A catalysis (40). A key feature of METTL14 is its
C-terminal RGG repeat sequence, which is critical for RNA substrate
recognition and accurate methylation site selection (41,42).
By serving as an RNA-binding scaffold, METTL14 acts as a critical
adaptor that notably enhances the catalytic efficiency of METTL3
(43).
Wilms' tumor 1-associating protein (WTAP) interacts
with the METTL3-METTL14 heterodimer and promotes its localization
to specific nuclear regions, particularly nuclear speckles
(44). WTAP serves as a key
regulatory component of the m6A methylation complex (45). Beyond its role in m6A regulation,
WTAP is involved in diverse biological processes, including
embryogenesis, cell cycle progression, differentiation, pre-mRNA
splicing and antiviral responses (45). Notably, WTAP serves a vital role in
the efficient recruitment of RNA substrates to the
methyltransferase complex. Although it lacks catalytic activity,
WTAP depletion can lead to a global reduction in m6A levels and
impaired RNA binding, thus underscoring its essential role in
maintaining m6A modification integrity (46).
m6A demethylases (erasers)
The FTO protein is an iron and
2-oxoglutarate-dependent dioxygenase that acts as an m6A
demethylase in eukaryotic cells, thereby contributing to the
dynamic regulation of RNA methylation (47). Its catalytic domain, located in the
N-terminal region, adopts a double-stranded β-helix (DSBH) fold
that is critical for demethylase activity (48). The C-terminal domain, composed of
α-helices, stabilizes the N-terminal conformation and activates
demethylation (8). Particular
domains, including loops such as the βI-βII loop, within the FTO
structure serve critical roles in RNA substrate recognition and
demethylation (9). In addition to
its role in RNA metabolism, FTO has been involved in obesity, type
2 diabetes and tumorigenesis (49),
highlighting its potential as a therapeutic target in metabolic and
neoplastic diseases.
ALKBH5 represents another major m6A demethylase that
primarily removes m6A marks from mRNA, thereby inversely regulating
RNA metabolism compared with writers. ALKBH5 commonly exerts
context-dependent effects on tumor initiation, progression and
metastasis via erasing m6A modifications (50). As a member of the
α-ketoglutarate-dependent dioxygenase family, the catalytic
activity of ALKBH5 relies on a conserved DSBH domain composed of
eight β-strands. Its nucleotide recognition lid (NRL), formed by
two β-hairpin loops (NRL1 and NRL2), is essential for substrate
recognition and the demethylation activity. The N-terminal region,
which encompasses multiple alanine residues and a unique helical
structure (51), contributes to
subcellular localization, whereas the C terminal domain, which is
enriched in arginine and serine, facilitates RNA binding.
Functionally, ALKBH5 regulates diverse cellular processes,
including proliferation, invasion and tumor growth. Its
dysregulation across different types of cancer highlights its
potential as a therapeutic target (11).
m6A binding proteins (readers)
m6A reader proteins recognize and bind to modified
RNA transcripts, thereby regulating multiple stages of RNA
metabolism, including stability, splicing, structural conformation,
nuclear export and translation. Major reader families include YTH
domain-containing proteins (YTHDFs, YTHDCs), insulin-like growth
factor 2 mRNA-binding proteins (IGF2BPs) and certain heterogeneous
nuclear ribonucleoproteins (hnRNPs) (52–54).
The IGF2BP family, comprising of IGF2BP1, IGF2BP2
and IGF2BP3, enhances the stability and translation efficiency of
m6A-modified mRNAs by recognizing and binding to m6A sites, thereby
regulating protein expression (55,56).
Dysregulation of IGF2BP members has been closely associated with
the onset, progression and metastasis of several types of cancer.
For instance, IGF2BPs can contribute to malignant phenotypes via
regulating m6A-modified transcripts (56).
Overall, m6A reader proteins serve a key role in
determining RNA fate through diverse mechanisms and subcellular
distribution patterns, thereby markedly affecting gene expression
networks. The role of m6A modification on melanoma invasion and
metastasis is predominantly mediated by these regulatory factors
(Fig. 1).
 | Figure 1.m6A methylation mechanism. m6A
methylation is catalyzed by a multi-component m6A methyltransferase
complex (‘m6A writers’), primarily composed of two main proteins,
namely METTL3 and METTL14, along with their regulatory cofactors,
such as WTAP. m6A methylation can be reversed by demethylases,
including FTO and ALKBH5 (‘m6A erasers’). m6A modifications can
affect RNA via recruiting m6A-binding proteins (‘m6A readers’),
such as YTHDCs and IGFBPs. m6A methylation is involved in several
processes associated with RNA metabolism, including RNA splicing,
localization, translation efficiency, stability and degradation.
m6A, N6-methyladenosine; METTL3, methyltransferase-like 3; WTAP,
Wilms' tumor 1-associating protein; FTO, fat mass and
obesity-associated protein; ALKBH5, AlkB homolog 5; YTHDCs, YTH
domain-containing proteins; IGF2BPs, insulin-like growth factor 2
mRNA-binding proteins. |
Impact of m6A regulators on tumor invasion
and metastasis
METTL3 in tumor invasion and
metastasis
Elevated METTL3 expression is commonly associated
with enhanced tumor invasion and metastasis through multiple
mechanisms. A previous study demonstrated that METTL3 could enhance
lung cancer cell proliferation via upregulation of
proliferation-associated genes such as c-Myc through m6A
modification, thereby facilitating early tumor expansion (57). In addition, METTL3 promoted
epithelial-mesenchymal transition (EMT), a critical process in
metastasis, via regulating the expression of EMT-inducing
transcription factors, including SNAIL (58) and zinc finger E-box-binding homeobox
1 (59). METTL3 also contributes to
immune escape via modulating immune-related genes. For example, a
study revealed that it enhanced m6A modification of programmed
death-ligand 1 (PD-L1) mRNA in breast cancer, thus enabling tumor
cells to evade immune surveillance and promoting metastasis
(60). Finally, METTL3 can also
promote a pro-tumorigenic microenvironment (TME) via regulating
intercellular communication and signaling pathways within the tumor
stroma, thus facilitating tumor progression (61).
Overall, METTL3 is recognized as a critical
regulator in multiple malignancies (62). Its upregulation in cancers such as
gastric cancer (63), bladder
cancer (3) and intrahepatic
cholangiocarcinoma (64) is
frequently associated with poor prognosis, highlighting its
potential as a therapeutic target. Targeting METTL3-mediated m6A
modifications can therefore represent a promising strategy for
inhibiting tumor progression.
METTL14 in tumor invasion and
metastasis
METTL14 serves a key role in tumor invasion and
metastasis primarily through its regulation by m6A modifications.
Particularly, it has been reported that METTL14 can regulate EMT.
For instance, METTL14 has been reported to regulate the expression
of EMT-related genes, such as RUNX2, via m6A modifications, thereby
affecting melanoma invasion and metastasis (6,7).
Furthermore, METTL14 exerts context-dependent
functions, acting as either an oncogene or a tumor suppressor.
However, its role in different types of cancer warrants further
mechanistic exploration. Liu et al (41) demonstrated that METTL14 expression
was regulated by several mechanisms, and its functional outcomes
varied across cancer types. Several factors may account for this
apparent contradiction. First, tissue-specific transcriptomic
landscapes determine METTL14 target selection; it preferentially
modifies oncogenic transcripts in pancreatic (65) and breast cancer (66), while regulating tumor suppressor
pathways in colorectal (67) and
liver cancers (5). Second, the
availability of cofactors could influence its activity; notably,
METTL3 and METTL14 exhibit consistent roles in some malignancies,
including acute myeloid leukemia and breast cancer, but opposing
roles in others, such as hepatocellular and gastric cancer
(41). For example, METTL14 has
been shown to suppress gastric cancer (68) and colorectal cancer (69). Third, cellular context and
microenvironmental conditions, such as hypoxia and inflammatory
signals, can further modulate the downstream effects of
METTL14-mediated m6A modifications. In melanoma, emerging evidence
has suggested that METTL14 function can be subtype-dependent, with
distinct roles observed in cutaneous vs. uveal melanoma (UM)
(6,7). Therefore, further studies are needed
to fully elucidate the context-dependent functions of METTL14.
In summary, the role of METTL14 in tumorigenesis is
complex and highly tissue-specific, thus affecting tumor invasion
and metastasis in a tissue-dependent manner via modulating the m6A
epitranscriptome of key regulatory genes.
WTAP in tumor invasion and
metastasis
In addition to METTL3 and METTL14, WTAP can also
affect cancer cell invasion and migration by modulating the
expression of EMT-related genes through m6A-dependent mechanisms.
For example, in liver cancer, increased WTAP expression is
associated with enhanced cell invasion and metastasis (70). As a component of the METTL3-METTL14
complex, WTAP can affect m6A modifications, stability and
translation efficiency of numerous critical tumor-related genes.
Its upregulation has been associated with the stabilization of
oncogenic mRNAs, thereby promoting tumor cell migration and
invasion (71).
ALKBH5 in tumor invasion and
metastasis
ALKBH5 has been reported to suppress tumor invasion
and metastasis via erasing m6A modifications from transcripts
encoding EMT-related genes. This reduction can reduce the stability
and translation of these genes, thereby attenuating the invasive
and metastatic potential of tumor cells. Such effects have been
previously observed in studies involving trophoblast cells and
melanoma (72) and gastric cancer
(73).
ALKBH5 is also involved in immune evasion via
modulating immune checkpoint expression. A previous study
demonstrated that ALKBH5 promoted PD-L1-mediated immune evasion via
demethylating ZDHHC palmitoyltransferase 3 mRNA, thus facilitating
glioma cell metastasis (74).
FTO in tumor invasion and
metastasis
FTO has been shown to promote melanoma tumorigenesis
and progression, in part through the regulation of genes involved
in cell proliferation, survival and metastatic potential (10). In addition, FTO serves a key role in
shaping the TME by regulating the expression of cytokines, growth
factors and other mediators. In lung adenocarcinoma, FTO modulated
immune cell function, angiogenesis and matrix composition, thereby
promoting tumor invasiveness (75).
Beyond its role in RNA demethylation, FTO is involved in metabolic
reprogramming; in breast cancer, it modulates energy and lipid
metabolism, which could indirectly support tumor growth and
metastasis (76).
IGF2BPs in tumor invasion and
metastasis
IGF2BPs facilitate tumor progression by stabilizing
specific target mRNAs in an m6A-dependent manner. For example, in
pancreatic ductal adenocarcinoma, IGF2BP stabilizes GLUT1 mRNA,
thereby promoting cancer cell proliferation and eventually
metastasis (77).
YTHDCs in tumor invasion and
metastasis
It has been also reported that YTHDC1 and YTHDC2 can
affect cell proliferation, migration and invasion via regulating
specific m6A-modified transcripts involved in key biological
processes such as cell cycle progression, cell adhesion and
motility (78,79) (Fig.
2).
Effect of m6A on melanoma migration and
invasion
Melanoma migration and invasion are critical
biological processes in which tumor cells dissociate from the
primary tumor, infiltrate surrounding tissues and ultimately
establish metastases at distant sites. These capabilities are
fundamental to melanoma progression and serve as major determinants
of patient prognosis. Highly invasive melanomas are more prone to
disseminate and metastasize to organs such as lymph nodes, lungs,
liver and brain (80,81). These metastatic lesions are
notoriously difficult to treat and are associated with poor
outcomes.
Therefore, a deep understanding of the molecular
mechanisms underlying the migration and invasion of melanoma cells
is critical for predicting disease course, guiding therapeutic
decision-making, and improving patient survival and quality of
life. Investigating such mechanisms could support the development
of novel therapeutic targets aimed at preventing metastasis.
Research on m6A modifications in
melanoma
Role of m6A modifications in melanoma
metastasis and invasion
METTL3 is commonly upregulated in melanoma and
serves a key role in melanoma cell proliferation, clonogenicity and
invasive potential (82). METTL3
silencing could impair cell viability, colony formation and
invasion, whereas its overexpression exerted the opposite effect.
Mechanistically, METTL3 overexpression promoted the accumulation of
pro-invasive proteins, including matrix metalloproteinase-2 and
N-cadherin, highlighting the importance of its m6A catalytic
activity. Other studies demonstrated that METTL3 knockdown
suppressed melanoma cell proliferation, migration and invasion, and
reduced tumor growth in xenograft models (83). A study by Chu et al (4) revealed that METTL3 knockdown decreased
m6A levels and the expression of the long non-coding RNA SNHG3.
SNHG3 acts as a molecular sponge for microRNA (miR)-330-5p, thereby
upregulating cellular nucleic acid binding protein (CNBP).
Restoration of SNHG3 counteracted the tumor-suppressive effects of
METTL3 depletion, and restored alterations in miR-330-5p and CNBP
levels. Clinically, SNHG3 expression was positively associated with
METTL3 and negatively with miR-330-5p, thus supporting the notion
that METTL3-mediated m6A modification of SNHG3 could promote
melanoma invasion and metastasis via the miR-330-5p/CNBP axis.
Role of WTAP in melanoma invasion and
metastasis
The role of WTAP in cancer development is gaining
increasing attention. Aberrant WTAP expression and function has
been closely associated with the pathogenesis of several types of
cancer, highlighting its potential as a therapeutic target.
Therefore, understanding the particular functions of WTAP in m6A
modifications and associated processes could provide novel insights
into the development of novel therapeutic strategies for improving
outcomes of patients with cancer (84).
Role of METTL14 in melanoma invasion
and metastasis
It has been reported that METTL14 contributes to
shaping the dynamic m6A landscape in choroidal melanoma (CM)
(6). It is closely associated with
activation of the Wnt/β-catenin signaling pathway (Wβ-CSP), a key
regulator of tumor cell migration, invasion and metastasis in CM
and other tumors. Notably inhibition of this pathway can suppress
the aforementioned biological processes (85). METTL14 expression is positively
associated with m6A levels. Therefore, METTL14 overexpression in CM
cell lines could activate Wβ-CSP and increase phosphorylated GSK3β.
Mechanistically, METTL14-mediated epigenetic changes promoted m6A
modifications within the 3′UTR of RUNX2, thereby facilitating CM
cell migration and invasion. By contrast, in UM, METTL14 expression
was suppressed by reduced histone acetylation. Notably, METTL14
silencing attenuated the antitumor effects of histone deacetylase
inhibitors both in vitro and in vivo, indicating that
METTL14 loss could inhibit ocular melanoma cell invasion and
migration (7,86).
Role of ALKBH5 in melanoma invasion
and metastasis
ALKBH5 serves a critical role in melanoma
progression. Liquid chromatography-mass spectrometry analyses
demonstrated that ALKBH5 overexpression reduced global m6A levels
in melanoma cells, suggesting it has a role in the progression of
skin cutaneous melanoma (SKCM) via m6A demethylation. Functionally,
ALKBH5 exhibits oncogenic properties in SKCM via promoting
migration, invasion, proliferation and clonogenicity, while
inhibiting autophagy, thereby driving tumor growth and metastasis
(14). Similarly, in UM, ALKBH5
expression is markedly upregulated, while its silencing has been
linked with reduced tumor growth in vivo. High ALKBH5
expression was also associated with poor prognosis in patients with
UM. Additionally, EP300-induced acetylation of histone H3 lysine 27
could increase ALKBH5 expression, while ALKBH5 knockdown suppressed
UM cell proliferation, migration and invasion, and induced
apoptosis in vitro. Mechanistically, ALKBH5 could promote
EMT through demethylating FOXM1, thereby enhancing its expression
and stability. Collectively, these findings identified ALKBH5 as a
potential prognostic biomarker and therapeutic target in UM
(16).
Role of FTO in melanoma invasion and
metastasis
FTO serves a pivotal role in the metabolic
adaptation of melanoma cells. Yang et al (10) systematically elucidated the
mechanism by which FTO could promote melanoma tumorigenesis and
mediate resistance to anti-programmed cell death protein 1
(PD-1/PDCD1) immunotherapy. Under metabolic stress conditions, such
as nutrient deprivation, FTO expression is increased through the
activation of the autophagy/NF-κB signaling pathway. As an m6A
demethylase, FTO can remove m6A modifications from PDCD1, C-X-C
motif chemokine receptor 4 (CXCR4) and SOX10 mRNAs. Under
physiological conditions, the m6A reader YTHDF2 binds to
m6A-methylated transcripts and promotes their degradation. However,
FTO-mediated demethylation can prevent YTHDF2 binding, thus
resulting in increased mRNA stability and subsequent elevated
protein expression of PD-1, CXCR4 and SOX10. This FTO/PD-1 axis
represents a critical component of metabolic stress adaptation in
melanoma cells. Immune checkpoint blockade has demonstrated
clinical efficacy in multiple malignancies (87,88),
and PD-1 may also exert melanoma cell-intrinsic functions (89). Notably, FTO knockdown could
sensitize melanoma to anti-PD-1 therapy in immunocompetent mouse
models, whereas this effect was abrogated in immunodeficient
NOD-scid IL2Rγ null mice suggesting dependence on adaptive
immunity. Additionally, FTO could confer resistance to IFNγ-induced
apoptosis; FTO depletion enhanced IFNγ-mediated apoptosis, whereas
FTO overexpression suppressed it (10).
Mechanistically, this pathway can be summarized as
follows: Metabolic stress → activation of the autophagy/NF-κB
pathway → upregulation of FTO → demethylation of PDCD1, CXCR4 and
SOX10 mRNAs → reduced YTHDF2-mediated decay → increased mRNA
stability → enhanced expression of PD-1, CXCR4 and SOX10 →
promotion of tumor growth and immune evasion → FTO knockout or
inhibition sensitizes melanoma to anti-PD-1 therapy (10).
Although direct experimental evidence for the
regulation of LAG-3 or TIM-3 by m6A modification in melanoma is
currently lacking, studies in other cancers have demonstrated that
m6A-related gene signatures are associated with the expression of
these alternative immune checkpoint molecules. For example, Ma
et al (90) reported that in
hepatocellular carcinoma, patients with a high m6A score exhibited
markedly upregulated lymphocyte activation gene 3 (LAG3) and T cell
immunoglobulin and mucin domain-containing protein 3 (TIM3)
expression, along with an immunosuppressive tumor microenvironment
characterized by abundant M2-polarized macrophages and regulatory T
cell infiltration. These findings suggest a potential link between
m6A modification and alternative immune checkpoints, which warrants
further investigation in melanoma.
Collectively, the aforementioned findings
demonstrate that m6A modifications shape the tumor immune
microenvironment and influence immunotherapy responses through
multiple mechanisms, including the regulation of chemokine
receptors (such as CXCR4), modulation of cytokine sensitivity (such
as IFNγ), alteration of immune cell infiltration patterns and
potential crosstalk with alternative immune checkpoints such as
LAG3 and TIM3. Thus, the impact of m6A on the immune landscape
extends well beyond the PD-1/PD-L1 axis.
Role of YTHDC1 and IGF2BP3 in melanoma
invasion and metastasis
The IGF2BP family (IGF2BP1/2/3) recognizes m6A
modifications and, in contrast to decay-promoting readers, enhance
target mRNA stability and translation in an m6A-dependent manner
(35). IGF2BPs have been implicated
in melanoma progression and metastasis, suggesting that they
represent potential therapeutic targets and may provide important
biological insights. For instance, IGF2BP3 interacts with the
circular RNA CDR1as, and the loss of CDR1as expression in melanoma
can permit IGF2BP3-mediated pro-metastatic activity, thereby
contributing to tumor invasion and metastasis.
Integrative analyses examining the associations
between IGF2BP3, other m6A regulators, tumor immunity and
metastasis have identified the metastasis-associated gene small
proline rich protein 1B (SPRR1B) as a key factor. SPRR1B, a member
of the small proline-rich protein family, is commonly altered in
melanoma and exhibits a notable inverse association with IGF2BP3
expression. Notably, a previous study (91) provided new perspectives on the
integrated role of m6A factors in SKCM and, for the first time,
identified SPRR1B as a promoter of melanoma cell proliferation,
invasion and migration.
In tumor immunity, the m6A regulators, including
YTHDC1, YTHDC2, WTAP and FTO, are strongly associated with immune
cell subtypes. Weighted gene co-expression network analysis
indicated that YTHDC1, YTHDC2 and WTAP were notably positively
associated with selected antitumor immune genes. WTAP, YTHDC1 and
YTHDC2 showed a broad positive association with immune-related
genes, whereas IGF2BP3 was broadly negatively associated,
implicating a potential role in immune evasion mechanisms in SKCM
(91,92).
Subtype-specific roles of m6A
regulators in melanoma
Melanoma encompasses heterogeneous molecular
subtypes characterized by diverse genetic drivers and clinical
behaviors, including BRAF-mutant, NRAS proto-oncogene, GTPase
(NRAS)-mutant, neurofibromatosis type 1-loss and triple-negative
subtypes, as well as site-specific variants, such as those in
cutaneous, uveal and mucosal melanoma. Emerging evidence has
suggested that m6A regulatory networks exhibit subtype-specific
functions across different contexts.
In BRAF-mutant melanoma, whether FTO directly
contributes to BRAF inhibitor resistance has not been clearly
established. However, FTO is known to be upregulated in melanoma
and promotes tumorigenesis through m6A-dependent
stabilization of key melanoma cell-intrinsic genes (10). Given that FTO-mediated demethylation
can enhance the expression of pro-survival factors, it is plausible
that FTO could activate alternative survival pathways, thereby
enabling tumor cells to bypass MAPK pathway inhibition. Further
studies are required to test this hypothesis. Similarly, METTL3 has
been reported to shape the tumor immune microenvironment and affect
therapeutic responses (93). ALKBH5
has been implicated in modulating the tumor microenvironment, thus
affecting responses to both targeted therapy and immunotherapy
(94).
In UM, distinct m6A signatures have been identified.
METTL14 promotes tumor cell migration and invasion through
m6A-mediated RUNX2 methylation (6),
while ALKBH5 drives tumor progression through demethylation of
FOXM1 (16). Notably, epigenetic
regulation differs between uveal and cutaneous melanoma; for
instance, histone acetylation status could differentially modulate
METTL14 expression across these subtypes (7,86).
With respect to immunotherapy, FTO expression levels
can serve as a predictive biomarker for response to anti-PD-1
therapy (10). Tumors with elevated
FTO expression exhibit increased PD-1 (PDCD1) expression and can be
less responsive to immune checkpoint blockade. However, this
association appears to vary among melanoma subtypes, potentially
due to differences in baseline immune infiltration and tumor
immunogenicity. Future studies should systematically characterize
m6A regulator expression and function across molecular subtypes to
identify context-dependent vulnerabilities and guide the
development of more precise therapeutic strategies.
Potential applications of m6A targeting in
melanoma therapy
Targeting the m6A modification machinery holds
promise for melanoma treatment. Due to the critical role of m6A
modifications in tumorigenesis (93,94),
and the documented dysregulation of key m6A-related proteins such
as METTL3 (93) and ALKBH5
(94) in melanoma, which both
associate with clinical features and patient prognosis, uncovering
the m6A regulatory network in this type of cancer could unveil
novel therapeutic targets. Potential therapeutic approaches include
inhibition of m6A methylation or modulation of the activity of
writers or erasers. However, further studies and clinical trials
are warranted to validate the safety and efficacy of the above
therapeutic approaches.
Conclusions and future perspectives
The present review systematically summarized the
emerging evidence implicating m6A RNA methylation in melanoma
invasion and metastasis. Accumulating data from the literature
indicated that m6A regulators, including writers (METTL3, METTL14,
WTAP), erasers (FTO, ALKBH5) and readers (IGF2BPs, YTHDCs), are
commonly dysregulated in melanoma and functionally contribute to
malignant progression through diverse mechanisms, including
enhanced proliferation, induction of EMT, modulation of immune
evasion and remodeling of the tumor microenvironment.
Several notable themes emerge from this body of
evidence. First, m6A regulators exhibit context-dependent functions
that vary across cancer types and even among melanoma subtypes.
METTL14 exemplifies this functional duality, acting as either an
oncogene or tumor suppressor depending on cellular context. Second,
m6A modifications serve a critical role in shaping responses to
immunotherapy through multiple mechanisms, with the FTO/PD-1 axis
representing a well-characterized pathway that is potentially
targetable (10). Third, m6A
regulators operate within an integrated network with potential
compensatory and feedback interactions that could influence
therapeutic outcomes.
Despite notable progress, several challenges and
knowledge gaps remain: First, subtype-specific heterogeneity
remains poorly explored. The majority of studies have treated
melanoma as a homogeneous entity. Future research should
systematically characterize m6A landscapes across BRAF- and
NRAS-mutant, and other molecular subtypes, as well as across
cutaneous, uveal and mucosal melanomas, to identify
subtype-specific vulnerabilities.
Second, compensatory mechanisms and network dynamics
are also poorly understood. The potential for feedback regulation
between writers and erasers, for instance whether METTL3 inhibition
could trigger ALKBH5 or FTO upregulation, remains largely
unexplored in melanoma. Notably, Panneerdoss et al (95) demonstrated in other cancer models
that METTL14 and ALKBH5 could reciprocally regulate each other,
eventually forming a positive feedback loop that could maintain m6A
homeostasis. Clarifying whether similar compensatory mechanisms
exist in melanoma warrants further investigation for guiding the
design of combination therapies.
Third, crosstalk with other RNA modifications should
not be excluded. While the present review focused on m6A, other RNA
modifications such as m5C and m1A also contribute to
epitranscriptomic regulation in cancer. Mao et al (96) comprehensively analyzed a total of
100 RNA modification regulators in lung adenocarcinoma and revealed
extensive expression associations and coordinated networks across
different modification systems, suggesting that these regulators
could collectively shape tumor microenvironment characteristics and
cancer hallmarks. Similarly, Qi et al (97) demonstrated notable cross-talk among
m6A, m5C, m1A and m7G regulators in soft tissue sarcoma, where a
network of 32 regulators exhibited extensive inter-modification
associations and distinct regulator clusters were characterized by
markedly different prognoses and TME landscapes. Therefore, it is
plausible that different RNA modifications (such as m6A, m5C and
m1A) do not act in isolation but jointly form a complex
epitranscriptomic regulatory network that drives malignant
progression. While direct evidence in melanoma is still lacking,
the extensive crosstalk observed in other cancers strongly supports
this hypothesis. Future integrated multi-omics approaches are
needed to decipher such synergistic networks in melanoma.
Fourth, clinical translation remains a notable
challenge. Although preclinical studies support targeting m6A
regulators in melanoma, the development of selective inhibitors
with favorable pharmacokinetic profiles is still at an early stage.
The safety and efficacy of these agents, particularly in
combination with immunotherapy or targeted therapy, require
rigorous evaluation in clinical trials.
Finally, developing novel biomarkers is of notable
importance. The potential of m6A regulator expression patterns or
global m6A modification levels as diagnostic, prognostic or
predictive biomarkers in melanoma warrants prospective validation
in large, well-annotated clinical cohorts.
In conclusion, m6A methylation has emerged as a
critical layer of epitranscriptomic regulation in melanoma invasion
and metastasis. Deciphering the complex m6A regulatory network,
with particular attention to context-specific functions, network
dynamics and therapeutic vulnerabilities, holds promise for
advancing the understanding of melanoma biology and for the
development of innovative treatment strategies. As the field
progresses toward precision oncology, integrating epitranscriptomic
profiling into melanoma management could enable more personalized
therapeutic approaches to improve patient outcomes.
Acknowledgements
Not applicable.
Funding
This work was supported by the Liaoning Provincial Science and
Technology Plan Joint Program (Natural Science Foundation-General
Project; grant no. 2024-MSLH-580).
Availability of data and materials
Not applicable.
Authors' contributions
ZhX, WY, JL, XC, SML, ZeX, QY and WX contributed to
the conception and design. ZhX and WY drafted the manuscript. JL,
XC and SML performed the literature search. ZeX and QY revised the
manuscript critically for important intellectual content. WX gave
final approval of the version to be published. All authors read and
approved the final version of the manuscript. Data authentication
is not applicable.
Ethics approval and consent to
participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests.
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