Introduction
Proline- and glutamine-rich splicing factor (SFPQ),
also known as polypyrimidine tract-binding protein
(PTBP)-associated splicing factor, was identified in 1993 during
the characterization of a complex of PTBPs that was hypothesized to
be important for early precursor mRNA splicing (1). SFPQ was subsequently named based on
its abundance of proline and glutamine. SFPQ is an RNA-binding
protein (RBP) and along with the nuclear proteins non-POU
domain-containing octamer-binding protein (NONO), paraspeckle
component 1 (PSPC1), it belongs to the conserved drosophila
behavioral human splicing (DBHS) family of proteins (2). Studies have shown that the three
proteins of this family are commonly found to be colocalized and
function in a variety of contexts by forming heterodimers. SFPQ is
primarily localized to paraspeckles (3), nuclear speckles (4), the nucleoplasm (5) and the nucleolus cap (6) within the nucleus. It possesses RNA-,
protein- and DNA-binding domains, which enable it to extensively
regulate the entire process of gene expression. This encompasses
transcriptional activation or repression, pre-mRNA splicing, mRNA
modification and internal ribosome entry site (IRES)-mediated
translation, among other functions (7–17).
Furthermore, SFPQ plays a role in DNA damage repair and affects
apoptosis (18–26). A growing body of evidence indicates
that it exerts a marked influence on cellular activity. Given its
extensive range of actions, SFPQ plays a notable role in regulating
the normal physiological functions of a multitude of cell types
within living organisms. Its dysregulation has been linked to the
onset and progression of a spectrum of diseases, including
neurodegenerative disorders and spinal muscular atrophy (27,28).
The protein was first discovered 30 years ago, and in recent years,
there has been an increase in studies indicating that the
dysregulation of SFPQ is linked to tumor development (29–33).
However, due to the wide range of targets and the complexity of its
role, the study of the function of SFPQ in tumors remains in the
preliminary stage of exploration. The present review primarily
focuses on the various specific molecules that SFPQ binds to and
regulates, as well as its role in different cancers.
The full-length protein of SFPQ is comprised of 707
amino acids, and at least seven structural domains have been
delineated thus far through the analysis of amino acid sequences
and functions (Fig. 1) (34). From the N-terminus, these are the
RGG box, the proline-rich domain, the two RNA recognition motifs
(RRMs), the NONA/paraspeckle (NOPS) structural domain, the
coiled-coil domain, the C-terminal domain (CTD) and a
Proline-RRM-linked domain that connects the proline-rich domains to
the RRMs. The RGG box is a 27-amino acid sequence located at the
N-terminal end of SFPQ. It comprises multiple trimeric RGG repeats
and has been demonstrated to confer RNA-binding activity.
Additionally, proteins containing RGG domains have been shown to
mediate interactions with DNA and proteins (34–38).
The RRM is widely found in a variety of RBPs. The
two RRMs contained in SFPQ play an important role in its normal
functioning. In addition to directly mediating RNA binding, RRMs
also mediate SFPQ interactions with other proteins (39,40)
and the subnuclear localization of SFPQ (4). The deletion of RRM2 results in the
diffuse accumulation and loss of nuclear speckle localization. The
NOPS domain is indispensable for the formation of paraspeckles.
Point mutations in this domain result in SFPQ losing its ability to
localize to paraspeckles (41).
Paraspeckles are membrane-less subnuclear bodies within the
nucleus, composed of the long non-coding RNA (lncRNA)
nucleus-enriched abundant transcript 1 (NEAT1) serving as a
molecular scaffold, which assembles with RBPs, including SFPQ and
NONO. They function by retaining specific mRNAs to modulate gene
expression and play important roles in cellular stress responses
(42). The coiled-coil domain
enables SFPQ to form dimers with other DBHS family proteins,
thereby facilitating the formation of paraspeckles (41). The domains of SFPQ indicate that
SFPQ is predominantly localized in the nucleus, where it performs a
series of functions by forming heterodimers with other DHBS
proteins to form paraspeckles.
SFPQ widely regulates gene expression
Regulation of epigenetics and gene
transcription
In normal cells, SFPQ exerts inhibitory or
activating effects on gene transcription by binding to various
proteins, including RNA polymerase II (9,10),
histone deacetylase (HDAC) (12,14,15,43)
and lysine-specific histone demethylase 1 (LSD1) (44). It has been demonstrated that the
binding of full-length SFPQ to the DNA-binding structural domain of
nuclear hormone receptors notably enhances the repressive effect of
the nuclear hormone receptor thyroid hormone receptors (TRs) and
retinoid X receptors on target genes in the absence of the hormone
ligand. Furthermore, it was determined that SFPQ binds to amino
acids 404–545 of paired amphipathic helix protein Sin3a (SIN3A),
which in turn recruits the SIN3A/HDAC complex to mediate the
transcriptional repression of the nuclear hormone receptor
(Fig. 2). This effect can be
reversed by the HDAC inhibitor sodium butyrate. Finally, the
aforementioned study found that SFPQ and SIN3A do not dissociate
from TR/retinoic acid receptor complex in vivo in the
presence of its ligand, suggesting that the intracellular
distribution and content of SFPQ may play a fine-tuning role in
this transcriptional repression (12).
 | Figure 2.Mechanism of SFPQ regulating gene
expression. A, SFPQ recruits epigenetic regulators, such as SIN3A
and HDAC, and represses gene expression. B, SFPQ undergoes
liquid-liquid phase separation with some transcriptional factors,
such as Smad4, thereby inhibiting gene expression mediated by the
Smad complex. C, SFPQ regulates alternative splicing. D, SFPQ is an
important component of paraspeckles, which responds to stress
conditions by RNA editing and RNA nuclear retention. E, SFPQ
mediates mRNA editing and subcellular localization. F, SFPQ takes
part in DNA repair. G, SFPQ is also a component of stress granule.
Created in https://BioRender.com. SFPQ, proline-
and glutamine-rich splicing factor; HDAC, histone deacetylase;
SIN3A, paired amphipathic helix protein Sin3a; TF, transcriptional
factor; P, phosphate group; NONO, non-POU domain-containing
octamer-binding protein; FUS, RNA-binding protein FUS; RBP, RNA
binding protein. |
In renal cell carcinoma (RCC), the transcriptional
repressor complex formed by SFPQ/transcription factor E2F1/HDAC1
has been demonstrated to mediate transcriptional repression of
multidrug and toxin extrusion protein 2 (MATE 2-K). MATE 2-K is
encoded by the gene solute carrier family 47 member 2
(SLC47A2), which plays a role in the secretion of certain
endogenous and exogenous compounds. Low expression of
SLC47A2 is associated with a poorer prognosis in RCC
(45). In 2016, it was indicated
that SFPQ binds to LSD1 and regulates the migration of nascent
pyramidal neurons in the developing cerebral cortex (44). LSD1, also known as KDM1A, is a
histone demethylase that functions as a transcriptional activator
or repressor of specific genes by forming complexes with various
proteins and catalyzing the demethylation of histone 3 lysine
residue 4 (H3K4) or H3K9 (46). In
the context of cortical development, the knockdown of LSD1 has been
shown to result in a transient delay in the migration of newborn
pyramidal neurons, accompanied by an increase in the number of
progenitor cells. The study validated the direct physical
interaction of SFPQ with LSD1 and discovered that neurons exhibit a
progressive increase in SFPQ expression as they migrate and
differentiate (47). Furthermore,
SFPQ depletion results in marked abnormalities in cell migration
within the brain and alters the proliferative behavior of
progenitor cells in the developing cerebral cortex (44). In tumor cells, LSD1 functions to
either promote or repress the transcription of
metastasis-associated genes through epigenetic regulation, thereby
facilitating the epithelial-mesenchymal transition process in a
variety of tumors, including breast cancer (48). Despite the lack of research
elucidating the direct interaction between SFPQ and LSD1 in tumors
and the impact of this interaction on the tumor genome, the present
review can serve as a valuable reference for studies examining the
regulation of LSD1 and SFPQ in tumors.
Furthermore, SFPQ has been suggested to have the
capacity to bind DNA directly, thereby exerting transcriptional
repression (49). Insulin-like
growth factor (IGF)-I functions as a transcription factor,
regulating the expression of genes containing IGF response elements
(IGFREs). SFPQ can bind to the 5′ end of the IGFRE GC box, thereby
inhibiting IGF-I-mediated gene transcription (50). In hypoxic conditions, the
expression of the lncRNA LHFPL tetraspan subfamily member
3-antisense RNA 2 (LHFPL3-AS2) is decreased in non-small cell lung
cancer (NSCLC). This results in a reduction in the binding of
LHFPL3-AS2 to SFPQ, leading to the release of free SFPQ and its
binding to the promoter of the gene thioredoxin-interacting
protein (TXNIP), which inhibits its expression.
TXNIP is a tumor suppressor gene that can inhibit the
expression of metastasis-associated genes through the TGF-β
signaling pathway. Consequently, the expression of TXNIP is
repressed when the concentration of free SFPQ is elevated, thereby
facilitating tumor migration and invasion (Fig. 3) (51).
SFPQ has also been demonstrated to bind to the
IL8 promoter, thereby repressing its transcription.
Furthermore, NEAT1 splicing variant 2 (NEAT1v2) expression has been
observed to increase during viral infection, which in turn induces
an increase in paraspeckle formation. The increase of NEAT1
expression induces the relocation of SFPQ from the IL8
promoter to the paraspeckle, thereby promoting the expression of
antiviral genes, such as IL8, C-X-C motif chemokine ligand 8
(CXCL8), antiviral innate immune response receptor
RIG-I and DEAD box protein 60 (16,52).
Additionally, the N6-methyladenosine (m6A) demethylase alkylated
DNA repair protein alkB homolog 5 (ALKBH5) is upregulated in
glioblastoma multiforme (GBM) under hypoxic conditions, resulting
in the erasure of m6A deposition in the lncRNA NEAT1. This process
stabilizes the transcript and facilitates NEAT1-mediated
paraspeckle assembly, which similarly leads to the relocation of
SFPQ from the CXCL8 promoter to the paraspeckle and
ultimately upregulates CXCL8/IL8 expression (53).
SFPQ promotes precursor mRNA splicing,
RNA processing and localization
SFPQ was initially identified in splicing-associated
complexes with important roles in early precursor mRNA splicing
(2). Subsequent studies have
elucidated the functions played by SFPQ in spliceosomal complexes.
In the nucleus of eukaryotic cells, upon transcriptional
activation, RNA polymerase II is enriched at the promoters of genes
to catalyze transcriptional elongation. Meanwhile, the CTD of RNA
polymerase II influences the removal of the first intron by
interacting with SFPQ, facilitating the efficient processing of
precursor mRNAs and coordinating transcription and mRNA processing
(54). Furthermore, the
death-inducer obliterator 3 amino-terminal of RNA polymerase II has
been observed to bind to histone and polymerase mandibular
structural domains, while its carboxy-terminus has been shown to
recruit SFPQ and facilitate the selective splicing of mRNAs. A
mutation in dido has been demonstrated to impede the binding of
SFPQ to RNAs and precipitate a considerable increase in the number
of exon skips (55).
It has been demonstrated that cells are able to
regulate intracellular protein reserves through variable splicing
in response to stimulation of external signals. Numerous studies
have reported the effects of SFPQ on the variable splicing of
different proteins. For instance, SFPQ has been shown to mediate
exon skipping of CD45 in order to regulate T-cell homeostasis and
activation (23). Under cellular
senescence, the autophagy receptor next to BRCA1 gene 1 protein
selectively degrades SFPQ, leading to enhanced skipping of exon 5
in the eukaryotic translation initiation factor 4H (EIF4H)
pre-mRNA. This splicing alteration drives proteome remodeling
associated with the senescence-associated inflammatory phenotype.
Furthermore, EIF4H alternative splicing has been linked to clinical
prognosis across multiple cancer types (56). Additionally, SFPQ has been observed
to bind with enhancer sequences on survival motor neuron protein
(SMN)2 exon 7, which promotes splicing and results in
the rapid degradation of SMNΔ7 (27). In tumor cells, SFPQ also affects
processes such as antitumor immunity and metastasis through
selective splicing. For instance, in hepatocellular carcinoma
(HCC), there is an increase in NONO expression, which is
accompanied by an interaction with SFPQ that promotes the inclusion
of exon 12a of Myc box-dependent interacting protein 1. This exon
inclusion exerts oncogenic activity (Fig. 4A) (57). In models including colorectal
cancer, melanoma and lymphoma, TGF-β has been shown to upregulate
SFPQ, which subsequently binds to Irf1 pre-mRNA to promote its
alternative splicing into the Irf1Δ7 isoform, thereby attenuating
Th1 cell activity (58). NONO
interacts with SFPQ to regulate exon jumping of SET domain and
mariner transposase fusion gene (SETMAR); the SETMAR-long isoform
can inhibit the transcription of metastasis-associated genes by
inducing trimethylated histone H3 at lysine 27 (H3K27me3) on their
promoters, thus inhibiting lymphatic metastasis of bladder cancer
cells (Fig. 4B) (59).
 | Figure 4.A schematic representation of SFPQ
regulating alternative splicing in cancer. (A) In normal liver
tissue, the long isoform of BIN1 is expressed at high levels and
suppresses c-Myc-induced downstream gene expression. In HCC,
upregulated SFPQ promotes exon 12a inclusion in BIN1 pre-mRNA,
shifting the BIN1 isoform balance towards the long isoform. This
increased abundance of the long BIN1 isoform stabilizes PLK1,
thereby promoting tumorigenesis. (B) In BCa, downregulation of SFPQ
promotes skipping of the second exon of SETMAR, increasing the
proportion of the short SETMAR isoform. This isoform shift reduces
H3K27me3 levels, leading to enhanced expression of
pro-metastatic genes and promoting metastasis. (C) In
platinum-resistant ovarian cancer cells, upregulated SFPQ mediates
the skipping of exons 4–7 in caspase-9 pre-mRNA. This promotes
accumulation of the anti-apoptotic long isoform of caspase-9,
resulting in enhanced cell survival. Created in https://BioRender.com. HCC, hepatocellular carcinoma;
BCa, bladder cancer; BIN1, bridging integrator 1; BIN1-S, BIN1
short isoform; BIN1-L, BIN1 long isoform; NONO, non-POU
domain-containing octamer binding; SETMAR, SET domain and mariner
transposase fusion gene; SETMAR-S, SETMAR short isoform; SETMAR-L,
SETMAR long isoform; SETD7, SET domain containing 7; PRDX4,
peroxiredoxin 4; GANAB, glucosidase II α subunit; SRSF2, serine and
arginine rich splicing factor 2; SFPQ, proline- and glutamine-rich
splicing factor; DHX9, ATP-dependent RNA helicase A; 12a, exon 12a
of c-Myc; PLK1, serine/threonine-protein kinase PLK1; caspase 9-S,
caspase 9 short isoform; caspase 9-L, caspase 9 long isoform;
H3K27me3, histone 3 lysine residue 27
trimethylation. |
As a prevalent modification of mRNAs, m6A
methylation occurs immediately after transcription of mRNA
precursors in the presence of methyltransferase-like 3. Conversely,
fat mass and obesity-associated protein (FTO) and ALKBH5 are
responsible for m6A demethylation. It has been demonstrated that
alterations in m6A modification patterns are linked to
tumorigenesis, including breast cancer, lung cancer, acute myeloid
leukemia and GBM (60). The m6A
modification may regulate mRNA splicing by interfering with the
interaction between splicing factors and mRNAs, affecting the
nuclear export of mRNAs, regulating mRNA translation and
influencing mRNA stability (61).
In 2020, it was demonstrated that SFPQ is an FTO-binding protein
that regulates substrate selection by FTO. The binding motif for
SFPQ is CUGUG, which enables SFPQ to recruit FTO and facilitate
demethylation at sites in close proximity to this motif. The data
indicate that FTO exhibits a preference for binding to CUGUG sites
in the presence of SFPQ compared with CUGUG sites in the absence of
SFPQ. This suggests that the selectivity of FTO for RNA is less
related to the CUGUG motif and more closely related to SFPQ. In
HeLa cells, the methylation of MYC and NEAT1v2 mRNA was markedly
reduced following SFPQ overexpression. These findings suggest that
in tumor cells, SFPQ may affect mRNA splicing, localization and
translation of oncogenes by determining the substrates of FTO
(62).
In addition to regulating alternative splicing and
modification of mRNAs, SFPQ modulates microRNA (miRNA)-mediated
post-transcriptional gene silencing by influencing both miRNA
biogenesis and activity (63). A
study demonstrated that SFPQ, as a constituent of the
miRNA-containing RNA induced silencing complex, specifically binds
to the 3′untranslated region (UTR) regions of select mRNAs and
modulates their folding. This structural regulation enhances the
silencing efficacy of specific miRNAs on these target mRNAs while
preventing stochastic nonproductive miRNA interactions (64).
Furthermore, SFPQ plays a role in the subcellular
transport of RNA. In neurons, SFPQ binds to kinesin family member
5A and kinesin light chain 1, which is responsible for
translocating mRNAs to axon terminals for localized protein
synthesis (65). Additionally,
SFPQ has been shown to mediate the export of estrogen receptor (ER)
mRNAs from the nucleus, thereby facilitating their translation in
breast cancer (66).
SFPQ affects IRES-mediated regulation
of translation
SFPQ plays a role in translation via the cytoplasmic
IRES, a complex secondary or tertiary RNA structure within mRNA
that facilitates ribosome assembly. SFPQ has been demonstrated to
bind directly to IRES elements within p53 (8). Furthermore, during TNF-related
apoptosis-inducing ligand-induced apoptosis, SFPQ has been shown to
regulate IRES-mediated translation of a range of apoptosis-related
genes (24). It is well documented
that mutations in the Ras protein are a common occurrence in a
number of different types of human cancer, including pancreatic
cancer, lung adenocarcinoma and colorectal carcinoma (CRC). The
activation of RAS mutations has been observed to result in the
promotion of tumor progression, with the regulation of gene
expression networks being a key factor in this process (67). It was observed that upon activation
of the Ras pathway, casein kinase 1α (CK1α) phosphorylates FOXO4
and promotes its proteasomal degradation, thereby inhibiting
FOXO4-mediated tumor suppression (68). In this process, SFPQ can bind to
the 5′UTR of CK1α mRNA, thereby promoting IRES-mediated translation
of CK1α (29).
SFPQ affects tumorigenesis and
progression
SFPQ has a regulatory role in
tumorigenesis
The loss of TGF-β-mediated cell growth inhibition at
the early stages of tumorigenesis represents one of the hallmarks
of cancer. This is characterized by the suppression of target genes
that are regulated by the Smad complex, which in turn promotes
tumor cell proliferation. Inhibition of the TGF-β pathway in some
tumors is caused by inactivating mutations or deletions of TGF-β
signaling components such as Smad4. However, such mutations are
less common in certain tumor types, indicating that there are
alternative mechanisms that lead to the inhibition of the TGF-β
signaling pathway (69).
It has been demonstrated that the overall survival
rate of patients with HCC and high expression of SFPQ is markedly
inferior to that of patients with HCC and low SFPQ expression.
Furthermore, the protein level of SFPQ has been shown to be
positively associated with the tumor size of patients with HCC, and
recurrence is frequently observed in patients with HCC and high
SFPQ expression. The lowest expression of SFPQ is observed in stage
I tumors, while the highest expression is seen in stage III and IV
tumors (32). The knockdown of
SFPQ was shown to inhibit the proliferation, migration and invasion
of HCC cells (32,33). Further analysis revealed that SFPQ
in HCC drives liquid-liquid phase separation (LLPS) through its
prion-like structural domain and binds to Smad4 through the
structural domain of the RGG box. The initial 27 amino acids at the
N-terminal end of the RGG box, referred to as the Smad-binding
domain, results in the formation of a droplet with Smad4, which
physically obstructs the formation of complexes between Smad4 and
Smad2, as well as Smad3, thereby triggering the dissociation of
Smad complexes. The deletion of SFPQ results in the upregulation of
Smad downstream target genes, including plasminogen activator
inhibitor 1 and cyclin-dependent kinase 4 inhibitor B, while the
expression of MYC is downregulated. This positively affects DNA
synthesis and the cell cycle, leading to the inhibition of tumor
cell proliferation (33).
Nevertheless, it should be noted that TGF-β exerts a dual
regulatory role in tumors, and that the aforementioned study only
explored the role of SFPQ/LLPS in the TGF-β growth inhibitory
signaling pathway and in the initiation stage of HCC, without
further investigation into the progression and metastasis. A
further study demonstrated that upon oncogenic activation in HCC,
mTOR complex 1 suppresses NEAT1v2 expression and parafollicular
biogenesis, resulting in the release of NONO/SFPQ. Subsequently,
NONO/SFPQ binds to U5 in the spliceosome, stimulating mRNA splicing
and the expression of key glycolytic enzymes, thereby enhancing
glucose transport, aerobic glycolytic flux, lactate production and
HCC proliferation and growth in vitro and in vivo
(70).
Furthermore, a study of CRISPR genome-wide knockdown
analysis of melanoma cells revealed that these cells exhibited a
high degree of dependency on SFPQ. This was evidenced by the
notable upregulation of SFPQ observed in tumor cells relative to
normal tissues. Additionally, knockdown of SFPQ was found to impede
proliferation, migration and glycolysis, as well as promote
apoptosis in tumor cells. Transcriptome analysis demonstrated that
SFPQ exerts a specific function as a positive regulator of the cell
cycle in melanoma, thereby promoting the expression of melanoma
proto-oncogene transcripts (71).
However, an alternative study from 2013 proposed that SFPQ
functions as a tumor suppressor protein, binding to the promoter of
the proto-oncogene Ras-related protein Rab23 (Rab23) to
repress its transcription (72).
Rab23 is a small GTPase and its overexpression has been linked to
enhanced tumor migration and invasion (73). The aforementioned study
demonstrated that the lncRNA Llme23 competes for binding to SFPQ,
having shown that upregulation of Llme23 results in SFPQ detachment
from the Rab23 promoter. This, in turn, leads to the upregulation
of proto-oncogene Rab23, thereby exerting a pro-oncogenic
effect (17,72). Therefore, SFPQ exhibits a
functional duality in melanoma. While serving as an important
survival factor that maintains malignant phenotypes, SFPQ
concurrently exerts tumor-suppressive activity by repressing
proto-oncogenes such as Rab23. This apparent contradiction
likely stems from tumor-intrinsic heterogeneity or
microenvironmental signaling variations. Future studies should
integrate spatial multi-omics and conditional gene-editing
technologies to decipher the molecular mechanisms governing the
functional switch of SFPQ within specific molecular contexts,
thereby enabling precise targeted therapeutic interventions.
In the context of transcriptional repression
initiated by physiological stressors such as UV, cold shock and
chemotherapy, SFPQ and NONO undergo LLPS to promote condensate
formation. During formation of condensates induced by transcription
inhibition, SFPQ remains associated with the active gene and
connects the active chromatin to the nucleolus, thereby altering
the spatial organization of the genome and increasing the number of
DNA double-strand breaks (DSBs) in the active gene. The erroneous
repair of these DSBs can lead to chromosomal translocations and the
subsequent generation of fusion oncogenes (74).
Effects of SFPQ on cell cycle and
apoptosis
The process of apoptosis, or programmed cell death,
is a normal physiological process. Tumor cells achieve rapid
proliferation through uncontrolled cell cycle progression and
inhibition of apoptosis. Following the application of
chemotherapeutic agents that promote DNA damage, tumor cells
develop acquired resistance through further promotion of DNA damage
repair and inhibition of apoptosis.
The depletion of SFPQ has been demonstrated to
exhibit synthetic lethality in CRC cells with the BRAFV600E
mutation (75). Activation of the
EGFR-RAS-MAPK signaling pathway is a common occurrence in CRC
(76,77). This cascade includes BRAF, a
serine/threonine protein kinase belonging to the RAF kinase family.
The BRAFV600E mutation results in a notable increase in the
activity of this protein. This in turn results in overactivation of
the MAPK pathway and the subsequent phosphorylation of nuclear
transcription factors, which induces the expression of genes
related to the cell cycle and cell proliferation. Additionally, the
MAPK pathway induces the phosphorylation of a variety of
intracellular kinases, thereby influencing cell proliferation and
adhesion. However, in the course of clinical treatment, the use of
RAF or MEK inhibitors often results in the development of
resistance through the reactivation of the MAPK pathway (78).
To overcome this resistance, a previous study
identified a synthetic lethality effect mediated by SFPQ deletion
through the construction of lentiviral interference libraries of
target proteins related to the nucleus of the MAPK pathway. One of
the defining characteristics of tumors is the loss of control of
the cell cycle and the accelerated proliferation of tumor cells. In
such conditions, the error rate of DNA replication increases, as
does the tolerance for replication errors. This replication
pressure further increases genomic instability (79). The aforementioned study indicated
that in BRAFV600E-mutated CRC cells, SFPQ is necessary for cellular
recovery from replication stress. When SFPQ is depleted, the
collision of DNA replication with RNA transcription, resulting in
the formation of R-loops, is increased, checkpoint kinase-1 (Chk1)
downstream of serine/threonine-protein kinase ATR (ATR) is
phosphorylated and a notable number of tumor cells are stalled in
the middle of the DNA replication in the S-phase, leading to
further apoptosis. The results of both in vivo and in
vitro experiments have demonstrated that tumor cell growth is
markedly inhibited in the presence of the BRAFV600E mutation and
SFPQ depletion. The authors of the aforementioned study therefore
concluded that the synthetic lethal effect of the BRAFV600E
mutation in combination with SFPQ depletion could be exploited
clinically to target ATR and Chk1, which are induced by SFPQ
depletion in CRC cells (75).
SFPQ promotes tumor drug
resistance
SFPQ has been demonstrated to influence the
resistance of certain hormone-related cancers to pharmacological
agents by modulating the processing of RNA. For instance, the
inhibition of the androgen-androgen receptor (AR) axis has been
demonstrated to effectively suppress prostate cancer. However, the
majority of patients ultimately develop resistance to AR splicing
variant 7 (AR-V7), which is produced by variable splicing and
results in constitutive expression. By contrast, SFPQ has been
shown to enhance the expression of various spliceosomal genes and
mediate the production of AR-V7 (80,81).
Similarly, in ER-positive breast cancer, SFPQ expression in tumor
cells is upregulated after endocrine therapy. This promotes
treatment resistance by mediating the nuclear translation of ERα
mRNA, which increases ER expression levels (66).
Platinum-based chemotherapeutic agents represent the
primary therapeutic option for patients diagnosed with ovarian
cancer. However, despite the initial efficacy of this treatment,
certain patients will experience tumor recurrence following
treatment. The primary mechanism of platinum resistance is
associated with the upregulation of DNA damage repair and the
inhibition of apoptosis in tumor cells (82). To investigate this further, a study
employed an unbiased gene loss-of-function screening approach to
knockdown 680 genes related to DNA damage repair, the p53 signaling
pathway and apoptosis. This resulted in a notable increase in the
sensitivity of tumor cells to platinum chemotherapeutic agents
following the knockdown of SFPQ. The expression of SFPQ was found
to be upregulated in platinum-resistant clinical samples of ovarian
cancer. Through pathway enrichment analysis, the study demonstrated
that SFPQ regulates alternative splicing in ovarian cancer cells,
specifically promoting exon 4–7 skipping of caspase-9 pre-mRNA to
generate the anti-apoptotic short isoform caspase 9-s, which
consequently reduces tumor cell apoptosis and contributes to
platinum resistance (Fig. 4C)
(83).
In previous years, an increasing number of studies
have indicated that targeting ferroptosis in tumor cells represents
a promising new avenue of research. However, the issue of drug
resistance inevitably arises during the application of ferroptosis
inducers to treat tumors. A previous study has identified the
mechanism of resistance to iron death inducers in GBM. The study
indicates that NF-κB activating protein recognizes the m6A site on
the cystine/glutamate reverse transporter protein (SLC7A11)
transcript, recruits SFPQ to splice at the transcription
termination site of the transcript and retains the last exon. This
process promotes the maturation of SLC7A11 mRNA and mediates the
resistance of tumors to iron-death-inducing agents (84).
SFPQ has also been demonstrated to contribute to the
development of chemoresistance by virtue of its involvement in the
DNA damage repair process. In triple-negative breast cancer (TNBC),
following etoposide treatment, SFPQ/NONO dimers form a complex with
insulin-like growth factor-binding protein 3 (IGFBP-3) to
participate in non-homologous end-joining repair, thereby repairing
DSBs caused by the application of chemotherapeutic agents and
leading to chemoresistance in TNBC. Furthermore, this repair
complex is known to also include components such as epidermal
growth factor receptor (EGFR) and DNA-dependent protein kinase
catalytic subunit (DNA-PKcs). Critically, the pharmacological
inhibition of EGFR and DNA-PKcs can impede the formation of the
IGFBP-3/NONO/SFPQ repair complex. Therefore, when inhibitors
targeting EGFR, DNA-PKcs and poly [ADP-ribose] polymerase are
employed in combination, they synergistically inhibit the DNA
damage repair process. This results in enhanced TNBC responsiveness
to platinum-based drugs (85).
GBM, a highly aggressive intracranial malignancy, is
commonly treated with temozolomide (TMZ) combined with
radiotherapy, which notably improves patient survival outcomes.
However, the majority of patients with GBM develop TMZ resistance
and tumor recurrence post-treatment, and no effective therapeutic
options currently exist for recurrent cases. Therefore, elucidating
the molecular mechanisms driving TMZ resistance and developing
novel therapeutic strategies are imperative (86). A study identified that the lncRNA
uncharacterized LOC729467 (HSD52) is overexpressed in TMZ-resistant
GBM cells. Through comprehensive investigations using in
vitro assays, intracranial xenograft models and GBM organoid
systems, researchers have demonstrated that HSD52 facilitates the
interaction between the RBPs SFPQ and NONO. This interaction
stabilizes RNA duplexes formed between HSD52 and E3 UFM1-protein
ligase 1 mRNA, leading to sustained activation of the DNA damage
repair pathway and ultimately promoting TMZ resistance in GBM
(87).
Furthermore, SFPQ plays an important regulatory role
in cancer progression and chemoresistance as a constituent of the
nuclear paraspeckle. The paraspeckle is a nuclear condensate formed
by lncRNA and NEAT1 and multiple RBPs (88,89).
Its discovery in HeLa cells in 2002 led to the elucidation of its
composition (90). SFPQ and NONO
bind to the CTD of NEAT1v2 as a heterodimer, which is important for
the recruitment of other proteins by NEAT1 and is important for the
formation of paranuclear (91–93).
The resulting paraspeckles have been demonstrated to facilitate the
retention of RNA through adenine-to-inosine editing, a
post-transcriptional modification that affects the structure,
stability, localization, translation and splicing of RNAs. This
function allows them to effectively fine-tune gene expression under
different physiological conditions (42).
An increasing number of studies have indicated that
stress signals from mitochondria and stress granules result in the
upregulation of NEAT1 transcription and an increased abundance of
nuclear paraspeckles (94), which
play a notable role in cancer development and chemoresistance
(95,96). For instance, in chronic myelogenous
leukemia (CML), diminished levels of the c-Myc protein are
important for the survival of CML cells (97). c-Myc interacts with and represses
the expression of the NEAT1 promoter, and in the context of reduced
c-Myc protein levels, the transcription of NEAT1 is enhanced,
leading to an increase in the formation of paraspeckle (88). SFPQ, an important component of
paraspeckle, was observed to be present in a free state within the
nucleus, where it inhibited free SFPQ-mediated apoptosis and
promoted CML cell survival (98).
The mucin 1βs ubunit (MUC1-C) in breast cancer upregulates the
expression of the RBPs SFPQ, NONO and RNA-binding protein FUS
(FUS), which are important for the formation of, paraspeckle
through the Myc pathway. Furthermore, MUC1-C increases the
expression of NEAT1 and RBPs through polybromo-associated BAF
complex-mediated chromatin accessibility. It was also observed that
MUC1-C co-localizes with SFPQ and FUS in the nucleus, and that the
downregulation of MUC1-C resulted in a decrease in the nuclear
level of SFPQ and an increase in the cytoplasmic level of SFPQ. The
MUC1-C/NEAT1 pathway confers chemoresistance and promotes the
cancer stem cell status of tumor cells, indicating that the
formation of paraspeckle increases stemness and chemoresistance in
tumor cells (99).
SFPQ as a biomarker to predict patient
prognosis in multiple tumors
A comparative analysis of differentially expressed
nuclear genes in NSCLC and lung fibrosis tissues revealed that SFPQ
is overexpressed in NSCLC, in addition to a unique 50-kDa short
isoform that is detected exclusively in the cytoplasm of lung
cancer cells. Promoter analysis of SFPQ revealed the presence of
three promoters upstream of SFPQ. Hypomethylation of promoter 2,
which is responsible for the short isoform, may be responsible for
the appearance of the short isoform in NSCLC (31). Nevertheless, further investigation
is necessary to elucidate the precise function of the cytoplasmic
short isoform of SFPQ in lung cancer and the specific influence of
elevated SFPQ expression on lung cancer development.
In CRC, a univariate Cox regression analysis
demonstrated a significant positive correlation between the
expression level of SFPQ and the overall survival of patients with
CRC [area under the curve (AUC), 0.901; confidence interval,
0.866–0.937] (100). Conversely,
another study indicated that patients with low SFPQ expression
exhibited shorter progression-free survival than patients with high
SFPQ expression (101).
Furthermore, using least absolute shrinkage and selection operator
Cox regression followed by multivariate Cox proportional hazards
analysis, researchers identified an eight-gene prognostic
signature, including SFPQ, from DNA repair-related genes in 1,096
patients with breast cancer. This model demonstrated significant
predictive value for overall survival (3-year AUC, 0.708; 5-year
AUC, 0.704) in the training cohort after adjusting for potential
confounders through multivariate analysis (102).
Summary and discussion
The current review discussed the effects of SFPQ on
tumor progression and drug resistance (Table I). In general, SFPQ can be used as
an independent predictor of prognosis in specific tumor types, such
as CRC. Additionally, SFPQ has been observed to exert oncogenic or
pro-oncogenic effects in various tumors and under different
environmental conditions. From a mechanistic perspective, SFPQ
affects the transcriptional activity of genes by binding to
histone-modifying enzymes in the nucleus or directly to DNA,
thereby playing an important role in regulating the splicing,
modification and localization of mRNA.
 | Table I.Summary of the roles and mechanisms
of SFPQ across various cancers. |
Table I.
Summary of the roles and mechanisms
of SFPQ across various cancers.
| First author,
year | Cancer type | Mechanism | Regulation
level | (Refs.) |
|---|
| Xiao et al,
2024 | HCC | Isolates Smad4 from
the Smad complex; inhibits TGF-β signaling | Transcription | (33) |
| Hu et al,
2020 | HCC | Exons contain
bridging integrator 1 |
Post-transcription | (57) |
| Bernard et
al, 2021 | HCC | Interferon
regulatory factor 1 splicing variant 7 alternative splicing |
Post-transcription | (58) |
| Zhang et al,
2022 | HCC | SFPQ promotes mRNA
splicing and upregulates the expression of key enzymes of
glycolysis |
Post-transcription | (70) |
| Bi et al,
2021 | SKCM | Increases oncogene
transcripts | Transcription | (71) |
| Zheng et al,
2017 | SKCM | Binding of the
Ras-related protein Rab23 promoter represses its transcription | Transcription | (72) |
| Klotz-Noack et
al, 2020 | CRC | Important for cells
to recover from replication stress | DNA repair | (75) |
| Zhang et al,
2018 | PDAC; CRC;
non-small cell lung cancer | Mediates internal
ribosome entry site translation of casein kinase 1α | Transcription | (68) |
| Kok et al,
2022 | PDAC; CRC;
non-small cell lung cancer | Mediates internal
ribosome entry site translation of casein kinase 1α | Transcription | (29) |
| Gao et al,
2019 | Kidney renal clear
cell carcinoma | Forms the
SFPQ/transcription factor E2F1/histone deacetylase 1 complex and
downregulates solute carrier family 47 member 2 transcription | Transcription | (45) |
| Xie et al,
2021 | Bladder
carcinoma | Mediates exon
skipping of SET domain and mariner transposase fusion gene |
Post-transcription | (59) |
| Song et al,
2020 | Cervical squamous
cell carcinoma | Mediates substrate
recognition by fat mass and obesity-associated protein |
Post-transcription | (62) |
| Mitobe et
al, 2020 | BRCA | Facilitates the
export of estrogen receptor α mRNA from the nucleus |
Post-transcription | (66) |
| de Silva et
al, 2019 | BRCA | Forms a complex
with insulin-like growth factor-binding protein 3 and mediating
non-homologous end joining | DNA repair | (85) |
| Takayama et
al, 2019 | PRAD | Increases androgen
receptor splice variant 7 through alternative splicing |
Post-transcription | (80) |
| Takayama et
al, 2017 | PRAD | Increases androgen
receptor splice variant 7 through alternative splicing |
Post-transcription | (81) |
| Pellarin et
al, 2020 | Ovarian
carcinoma | Increases
anti-apoptotic splicing forms of caspase |
Post-transcription | (83) |
| Sun et al,
2022 | GBM | NF-κB activating
protein recognizes m6A of solute carrier family 7 member 11,
recruiting SFPQ to promote the maturation of pre-mRNA |
Post-transcription | (84) |
| Dong et al,
2021 | GBM | SFPQ relocates from
C-X-C motif chemokine ligand 8 promoter to paraspeckle and
upregulates IL8 | Transcription | (53) |
It is noteworthy that SFPQ plays a role in the
formation of nuclear paraspeckles through LLPS. This process is
associated with tumor stemness and drug resistance, as it affects
protein abundance under stress conditions, including through RNA
retention. Concurrently, the prevalence of paraspeckles exerts an
influence on the quantity of free SFPQ within the nucleus,
consequently impacting the function of SFPQ in the regulation of
transcription on chromatin. It is therefore evident that the
specific impact of SFPQ on tumor cells cannot be generalized;
rather, a comprehensive analysis of the distribution of SFPQ in the
nucleus, as well as the regulation of its function and localization
by post-translational modifications of SFPQ itself, is
required.
The RBP NONO is well-documented to exert its
biological functions through heterodimerization with SFPQ.
Accumulating evidence indicates that NONO is frequently upregulated
in tumor tissues, where it acts as an oncoprotein to drive
tumorigenesis via diverse molecular mechanisms. Previous studies
have challenged the paradigm of functional synergy between NONO and
SFPQ, revealing context-dependent antagonistic roles of these two
proteins. The precise functional interplay and molecular basis
underlying their cooperative or opposing activities remain to be
fully deciphered (33,63).
As detailed in the present review, SFPQ exhibits
both DNA- and RNA-binding activities and interacts with a range of
proteins. Consequently, it primarily functions as a molecular
scaffold in the nucleus, influencing gene expression by
coordinating the binding of diverse RNAs, DNAs and proteins.
Additional investigation is required to elucidate the way SFPQ
responds to disparate external stimuli, including hypoxia and
stress, in order to achieve precise nuclear localization and
facilitate binding to various proteins, thereby exerting
differential regulatory effects on gene expression.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
Not applicable.
Authors' contributions
SZ and ZL conceptualized the present review. SZ
reviewed the data and wrote the manuscript. LF provided
supervision. SZ, ZL and LF reviewed and edited the manuscript. All
authors read and approved the final 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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