Cancer Letters 357 (2015) 55–62

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Cancer Letters
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c a n l e t

Mini-review

SALL4: An emerging cancer biomarker and target

Xu Zhang a,1,**, Xiao Yuan a,1, Wei Zhu a, Hui Qian a, Wenrong Xu a,b,*
a Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013,

China
b
The Affiliated Hospital, Jiangsu University, 228 Jiefang Road, Zhenjiang, Jiangsu 212001, China

A R T I C L E I N F O A B S T R A C T

Article history: SALL4 is a transcription factor that plays essential roles in maintaining self-renewal and pluripotency of
Received 30 September 2014 embryonic stem cells (ESCs). In fully differentiated cells, SALL4 expression is down-regulated or si-
Received in revised form 17 November lenced. Accumulating evidence suggest that SALL4 expression is reactivated in cancer. Constitutive expression
2014
of SALL4 transgene readily induces acute myeloid leukemia (AML) development in mice. Gain- and loss-
Accepted 17 November 2014
of-function studies reveal that SALL4 regulates proliferation, apoptosis, invasive migration, chemoresistance,
and the maintenance of cancer stem cells (CSCs). SALL4 controls the expression of its downstream genes
Keywords:
through both genetic and epigenetic mechanisms. High level of SALL4 expression is detected in cancer
Stem cell factor
SALL4 patients, which predicts adverse progression and poor outcome. Moreover, targeted inhibition of SALL4
Cancer has shown efficient therapeutic effects on cancer. We have summarized the recent advances in the biology
Biomarker of SALL4 with a focus on its role in cancer. Further study of the oncogenic functions of SALL4 and the
Target underlying molecular mechanisms will shed light on cancer biology and provide new implications for
cancer diagnostics and therapy.
© 2014 Elsevier Ireland Ltd. All rights reserved.

Introduction served in both hematological diseases and solid tumors, including

SALL4 (sal-like 4) is a member of the mammal homologs of Dro-
sophila homeotic gene spalt (sal). In humans, SALL4 gene mutations
are known to cause Okihiro syndrome (Duane radial ray syn-
drome), an autosomal dominant disease involving multiple organ
defects [1–4]. In mice, SALL4 homozygous knockout is embryonic
lethal and SALL4 heterozygous knockout causes dysplasia of mul-
tiple organs [5,6]. SALL4 is an essential factor for the maintenance
of self-renewal and pluripotency of embryonic stem cells (ESCs) [7,8].
SALL4 expression gradually decreases with the maturation of tissues
and organs. However, SALL4 expression is found to be restored in
numerous human malignancies. High levels of SALL4 has been ob-
acute myeloid leukemia, chronic myeloid leukemia, breast cancer,
lung cancer, gastric cancer, colorectal cancer, liver cancer, endome-
trial cancer and glioma. SALL4 acts as an oncogene that plays
multifaceted roles in the processes of cancer initiation, develop-
ment, and progression. Exploring the underlying mechanisms
responsible for the oncogenic functions of SALL4 will allow the de-
velopment of a novel target for cancer therapy. In this review, we
focus on recent progress in understanding the roles of SALL4 in
cancer and the molecular mechanisms, with an emphasis on the
potential of SALL4 in cancer diagnostics and treatment.
Roles of SALL4 in stem cells

Abbreviations: ESCs, embryonic stem cells; AML, acute myeloid leukemia; CSCs,
cancer stem cells; iPS, induced pluripotent stem cell; HSCs/HPCs, hematopoietic stem/
progenitor cells; MDS, myelodysplastic syndrome; LSCs, leukemic stem cells; CML,
chronic myeloid leukemia; MLL, mixed-lineage leukemia; EMT, epithelial–
mesenchymal transition; SP, side population; HpSC-HCC, hepatic stem cell-like
hepatocellular carcinoma; TKI, tyrosine kinase inhibitor; NuRD, nucleosome remod-
eling deacetylase; HDAC, histone deacetylase; DNMT, DNA methyltransferase; LSD1,
lysine-specific demethylase 1; PRC, polycomb repressive complex; GCT, gem cell
tumor; CRC, colorectal carcinoma; ESCC, esophageal carcinoma; SBHA, suberic bis-
hydroxamic acid; TSA, trichostatin; TAT, transactivator of transcription.
* Corresponding author. Tel.: +86 511 85038215; fax: +86 511 85038449.
E-mail address: icls@ujs.edu.cn (W. Xu).
** Corresponding author. Tel.: +86 511 85038215; fax: +86 511 85038449.
E-mail address: xuzhang@ujs.edu.cn (X. Zhang).
1 These authors contributed equally to this paper.
SALL4 has two isoforms, SALL4A and SALL4B, which resulted from
different internal splicing patterns in exon 2 (Fig. 1). SALL4A and
SALL4B are able to form homodimers or heterodimers with dis-
tinct DNA binding sites and exhibit different roles during early
embryogenesis [9]. In murine ESCs, depletion of both isoforms of
SALL4 by shRNA leads to multilineage differentiation. SALL4A and
SALL4B have overlapping, but not identical binding sites of epigen-
etic marks in target loci or their interactions with other pluripotent
factors. In addition, SALL4B, but not SALL4A, alone can maintain the
pluripotent state of mouse ESCs. SALL4 expression could be de-
tected in embryos as early as at the 4-cell stage and is gradually
restricted to inner cell mass from which ESCs are normally derived.
Disruption of both SALL4 alleles cause embryonic lethality
during peri-implantation and depletion of SALL4 results in early

http://dx.doi.org/10.1016/j.canlet.2014.11.037
0304-3835/© 2014 Elsevier Ireland Ltd. All rights reserved.
56 X. Zhang et al./Cancer Letters 357 (2015) 55–62

Fig. 1. SALL4 gene and protein structure. Human SALL4 gene localizes on chromosome 20q13.13-q13.2 and consists of four exons. The human SALL4 protein has multiple
zinc finger (ZF) domains of the SAL type, which is composed of one N terminal C2HC type zinc finger (NT ZF) and seven C2H2 type zinc fingers. A Q rich motif is responsible
for interactions between members of SALL1-4. The SALL4 protein has two isoforms, SALL4A and SALL4B, which resulted from different internal splicing patterns in exon 2.
SALL4B lacks the 386 to 822 amino acids of full-length SALL4 protein. A conserved “KRLR” motif at amino acid positions of 64–68 is identified in both SALL4A and SALL4B
as nuclear localization signal (NLS).

embryonic development defects, suggesting that SALL4 is critical
for early embryonic development.
SALL4 plays a vital role in stem cell self-renewal and pluripotency
through multiple layers of mechanisms. First, SALL4 regulates the
activation of several important signaling pathways in stem cells. Ac-
tivation of Wnt/β-catenin signaling maintains the pluripotency of
human and mouse embryonic stem cells [10]. SALL4 binds to
β-catenin and up-regulates the expression of the target genes of the
Wnt/β-catenin pathway [11], suggesting that SALL4 may promote
stem cell self-renewal and inhibit stem cell differentiation through
the interaction with β-catenin. STAT3 activation mediates the self-
renewal and pluripotency of embryonic stem cells [12]. SALL4 may
interact with STAT3 to regulate the self-renewal and differentia-
tion of stem cells. The Hedgehog signaling pathway plays a pivotal
role in organogenesis and differentiation during development [13].
Genome-wide analysis reveals that SALL4 regulates Sonic Hedge-
hog (SHH) pathway [7]. SALL4 may modulate SHH signaling to
prevent the differentiation of embryonic stem cells. SALL4 inhibits
the expression of PTEN and induces the activation of the Akt pathway
[14], which may enhance stem cell self-renewal and expansion and
maintain stem cells at undifferentiated state. Second, SALL4 modu-
lates the transcription of key stemness factors including Oct4, Nanog,
Sox2, and c-Myc [7,15–17]. Compared to wild type ESCs, the ex-
pression of these 4 genes is remarkably down-regulated in SALL4+/−
ESCs [7], suggesting that SALL4 could be a key regulator for stem
cell factors. SALL4 can activate the expression of Oct4, Nanog, Sox2,
and c-Myc and form a transcriptional core network with these factors
to maintain cell stemness. The down-regulation of core stemness
factors may be responsible for SALL4 knockdown-induced sponta-
neous cell differentiation [18]. Due to its critical role in maintaining
pluripotency, SALL4 has been used as an enhancer for induced plu-
ripotent stem cell (iPS) generation from somatic cells [19]. Third,
SALL4 may regulate the expression of key genes that are associ-
ated with stem cell self-renewal and differentiation through
epigenetic modulation. SALL4 induces the activation of Bmi-1, an
important factor for regulating stem cell self-renewal, by mediat-
ing H3K4 trimethylation and H3K79 dimethylation at the promoter
region [20]. In addition, SALL4 recruits MLL (mixed lineage leuke-
mia), a histone methyltransferase, to prompt H3K4 and H3K79
methylation, resulting in HOXA9 up-regulation [21]. In summary,
these findings indicate that SALL4 is involved in regulating self-
renewal and pluripotency of stem cells through a variety of signaling
pathways, transcription factors, and epigenetic modulators.
SALL4 expression has also been found in adult stem/progenitor
cells. In human bone marrow, SALL4 expression is strictly limited
to the CD34+ hematopoietic stem/progenitor cells (HSCs/HPCs) and
decreased following differentiation [22,23]. SALL4 is found to be a
robust stimulator for both human and mouse HSC/HPC self-
renewal [24,25]. Human HSCs transduced with SALL4 are able to
expand rapidly and efficiently in vitro. On the contrary, depletion
of endogenous SALL4 leads to reduced HSC proliferation and ac-
celerated cell differentiation. SALL4 regulates the expression of genes
that are critical in maintaining short-term and long-term HSC pro-
liferation, including Bmi-1, HOXA9, and c-Myc [26]. SALL4 works
with these factors to form a concerted network for normal hema-
topoiesis [27]. In addition to HSCs/HPCs, SALL4 is expressed in fetal
hepatoblasts but silenced in adult hepatocytes [28]. The expres-
sion levels of SALL4 gradually fall during liver development. SALL4
overexpression enhances while SALL4 knockdown impairs induced
differentiation of hepatoblasts to cholangiocytes and the forma-
tion of bile duct, suggesting that SALL4 regulates cell fate decision
in fetal hepatic stem/progenitor cells.
Roles of SALL4 in cancer
SALL4 is overexpressed in cancer and affects multiple cellular pro-
cesses which are involved in tumorigenesis, tumor growth and tumor
progression. SALL4 regulates a variety of targets in distinct types
of cancer cells. In this section, we review the targets of SALL4 and
their functions in cancer (Fig. 2).
SALL4 and cell transformation
During normal hematopoiesis, SALL4 is expressed in the CD34+
HSC/HPC population. SALL4 expression is down-regulated or si-
lenced in mature blood cells. In contrast, SALL4 is constitutively
expressed in human primary acute myeloid leukemia (AML) and
myeloid leukemia cell lines. To test whether constitutive expres-
sion of SALL4 is sufficient to induce AML, Ma and colleagues generated
a SALL4B transgenic mouse model with SALL4B expression in most
organs. They demonstrated that all the monitored SALL4B trans-
genic mice exhibit dysregulated hematopoiesis and develop
 X. Zhang et al./Cancer Letters 357 (2015) 55–62 57

Fig. 2. Proposed model for SALL4 regulatory network in cancer. SALL4 regulates cell proliferation, apoptosis, migration/invasion, drug resistance, and stemness by targeting
a variety of genes. SALL4 regulates cell proliferation through the β-catenin/cyclin D1, Bmi-1, and PTEN pathways. SALL4 regulates cell migration/invasion through the ZEB1/
E-cadherin and the c-Myc pathways. SALL4 inhibits apoptosis through the Bmi-1, HOXA9, and FADD pathways. SALL4 regulates the resistance of cancer cells to chemotherapy
by targeting the ABCA3, ABCG2, and c-Myc pathways. SALL4 regulates the self-renewal of cancer stem cells through the Oct4, Nanog, Sox-2, and Bmi-1 pathways. STAT3,
CDX1, and TCF/LEF are upstream positive regulators of SALL4. SALL4 is a downstream target of microRNA-107. Natural compounds matrine and apigenin could inhibit the
expression of SALL4.

myelodysplastic syndrome (MDS)-like features at ages 6–8 months
and half of the monitored mice eventually progressed to AML [11].
Mice injected with serially transplanted SALL4B-induced AML cells
also develop aggressive AML, suggesting that SALL4B-induced AML
is transplantable. The potential signaling pathway that SALL4 may
affect in leukemogenesis has been postulated, which includes SALL4
binding to β-catenin and activating the Wnt/β-catenin signaling
pathway. The expression of Wnt/β-catenin downstream target genes,
such as c-Myc and Cyclin D1, is upregulated in SALL4B transgenic
mice. Thus, constitutive expression of SALL4 in AML may enable leu-
kemic blasts to gain stem cell properties, such as self-renewal and/
or lack of differentiation, and thus become leukemic stem cells (LSCs).
In addition, Bmi-1 is identified as a target gene for SALL4 in both
hematopoietic and leukemic cells [20]. Bmi-1 is a putative onco-
gene that modulates stem cell pluripotency and plays a role in
leukemogenesis. SALL4 binds to Bmi-1 promoter and directly affects
the levels of endogenous Bmi-1 expression. In vitro knockdown of
SALL4 by siRNA in leukemic cells or in vivo deletion of one copy of
SALL4 in mouse bone marrow significantly reduces Bmi-1 expres-
sion. Bmi-1 expression is up-regulated in transgenic mice that
constitutively overexpress SALL4B, and the levels of Bmi-1 in these
mice increase as they progress from normal to preleukemic
(myelodysplastic syndrome) and leukemic (acute myeloid leuke-
mia) stages. Furthermore, there is a strong positive correlation
between SALL4 and Bmi-1 expression in human AML samples. SALL4
induces high levels of H3K4 trimethylation and H3K79 dimethylation
in the binding region of the Bmi-1 promoter, suggesting that SALL4
provides epigenetic modifications at the Bmi-1 gene promoter. These
findings indicate a link between SALL4 and leukemogenesis by regu-
lating self-renewal of leukemic stem cells.
SALL4 and cell proliferation and apoptosis
SALL4 acts as a key regulator of cell proliferation and apoptosis
in cancer cells. SALL4 knockdown induces massive apoptosis and
significant growth arrest in human leukemic cells [29]. In addi-
tion, reduction of SALL4 markedly diminishes tumorigenicity of
human leukemia cells in immunodeficient mice. ChIP-chip assay for
the global gene target of SALL4 in human leukemic cells reveals that
SALL4 binds to the promoter of genes that are critically involved
in apoptosis. The expression levels of these genes change signifi-
cantly after SALL4 knockdown, indicating that SALL4 is a key
regulator of apoptosis-associated genes. In addition, SALL4 has an
important role in the proliferation and survival of chronic myeloid
leukemia (CML) cells, and its expression is associated with an ad-
vanced stage of CML disease. Downregulation of SALL4 leads to cell
cycle arrest and apoptosis in CML cells [30]. In AML and CML cells,
SALL4 knockdown-induced apoptosis and cell cycle arrest are rescued
by forced expression of Bmi-1, suggesting that SALL4 regulation of
Bmi-1 may at least be partially responsible for its effects on cell pro-
liferation and apoptosis. Moreover, HOXA9 is identified as another
downstream target of SALL4 [21]. SALL4 interacts with mixed-
lineage leukemia (MLL) and co-occupies the HOXA9 promoter region
in AML leukemic cells. Compared with wild-type controls, HOXA9
is up-regulated in SALL4B transgenic mice. In primary human AML
cells, downregulation of SALL4 also reduces HOXA9 expression and
induces cell apoptosis. Furthermore, SALL4 knockdown leads to
growth inhibition of lung cancer cells as a result of cell cycle arrest
[31]. Similarly, reduction of SALL4 expression by siRNA com-
pletely also inhibits the proliferation of breast cancer cells as a result
of cell cycle arrest [32]. Conversely, SALL4-overexpressing liver cancer
58 X. Zhang et al./Cancer Letters 357 (2015) 55–62
cells exhibit enhanced cell proliferation with the characteristics of
reduced cell population in the G1 phase through the up-regulation
of cyclin D1 and D2 [33]. In contrast, down-regulation of SALL4 in-
hibits liver cancer cell proliferation in vitro as well as in tumor
xenograft models. We have recently reported that SALL4-
overexpression enhances while knockdown of SALL4 inhibits the
proliferation of gastric cancer cells [34]. In consistent with this ob-
servation, SALL4 knockdown also inhibits endometrial cancer cell
growth in vitro and tumorigenicity in vivo due to the inhibition of
cell proliferation and increased apoptosis [35].
SALL4 and invasive migration
The research from our group has indicated that the SALL4 level
is highly correlated with lymph node metastasis of gastric cancer
[34]. Enforced expression of SALL4 enhances the migration of human
gastric cancer cells, whereas knockdown of SALL4 by siRNA leads
to the opposite effects. SALL4 overexpression up-regulates the ex-
pression of Twist1, N-cadherin while down-regulating E-cadherin
expression, thus inducing epithelial–mesenchymal transition (EMT)
in gastric cancer cells. In endometrial cancer, downregulation of
SALL4 significantly impedes the migration and invasion proper-
ties of cancer cells in vitro and their metastatic potential in vivo [35].
SALL4 specifically binds to the c-Myc promoter region in endome-
trial cancer cells. Reduction of SALL4 leads to a decreased expression
of c-Myc and ectopic SALL4 overexpression causes increased c-Myc
expression, indicating that c-Myc is one of the SALL4 downstream
targets in endometrial cancer. In addition, SALL4 suppresses
E-cadherin expression and maintains cell dispersion in basal-like
breast cancer [36]. SALL4 inhibits intercellular adhesion and main-
tains cell motility after cell–cell interaction and cell division, which
results in the dispersed phenotype. SALL4 knockdown leads to EMT
in basal-like breast cancer cells. Further study showed that SALL4
positively regulates the EMT factor ZEB1, therefore suppressing
E-cadherin transcription and leading to cell dispersion and mes-
enchymal gene expression.
SALL4 and cancer stem cells
SALL4 is essential for maintaining the properties of cancer stem
cells (CSCs). The expression of SALL4 is significantly higher in side
population (SP) cells than that in non-SP cells in leukemia cell lines,
suggesting that SALL4 is more abundant in CSCs [37]. Knockdown
of SALL4 leads to reduced frequency of SP cells, indicating that SALL4
is required for the self-renewal of cancer stem cells. Similarly, SALL4
is also enriched in SP of breast cancer cells and increased SALL4 ex-
pression leads to an expansion of SP subset in breast cancer cells.
We have recently demonstrated that SALL4 overexpression induces
the acquirement of stemness in gastric cancer cells through in-
creasing the levels of Sox2, Bmi-1, CD133, and Lin28B [34]. SALL4-
overexpressing gastric cancer cells could be efficiently induced to
differentiate into osteoblasts and adipocytes under the appropri-
ate conditions, suggesting that SALL4 overexpression endows gastric
cancer cells with stemness and pluripotency. SALL4 is suggested as
a stem cell marker in liver cancer that regulates the stemness of liver
cancer cells [33]. SALL4 overexpression down-regulates differenti-
ation markers ALB, TTR, and UGT2B7, suggesting that SALL4 inhibits
hepatocytic differentiation in human liver cancer cells. SALL4 is iden-
tified as one of the transcription factors that are potentially activated
in hepatic stem cell-like HCC (HpSC-HCC) [38]. SALL4-positive HCCs
are associated with expression of the hepatic stem cell markers in-
cluding EpCAM. EpCAM+ cells have higher expression of SALL4 and
possess a stronger spheroid formation capacity than EpCAM− cells,
indicating that SALL4 is activated in EpCAM+ liver CSCs. Ectopic ex-
pression of SALL4 leads to up-regulation of the hepatic stem cell
markers and down-regulation of the mature hepatocyte marker.
Moreover, SALL4 overexpression results in the significant activa-
tion of spheroid formation while knockdown of SALL4 results
in a compromised spheroid formation capacity with decreased ex-
pression of EpCAM, suggesting that SALL4 regulates stemness of
HpSC-HCC.
SALL4 and chemoresistance
SALL4 expression is associated with therapy response in cancer.
In acute myeloid leukemia (AML), SALL4 expression is higher in drug
resistant patients than those from drug-responsive cases. AML cells
with decreased SALL4 expression are more sensitive to drug treat-
ments than their parental cells. SALL4 modulates drug sensitivity
through the maintenance of SP cells in AML [37]. SALL4 directly binds
to the promoter region of ABCA3, a resistance-mediating trans-
porter, affecting the formation of SP cells in AML. SALL4 expression
is positively correlated to that of ABCA3 in primary leukemic patient
samples. In addition to AML patients, constitutive expression of SALL4
has also been observed in CML cells in the blast crisis or acceler-
ated phase. Exposure to tyrosine kinase inhibitors (TKI) leads to
increased expression of SALL4 in CML cells, which consequently up-
regulates ABCA3 [39]. High ABCA3 levels facilitate detoxification of
TKI, protecting CML cells against TKI effects. The positive regula-
tion of ABCA3 through SALL4 constitutes an autoprotective loop to
protect CML cells from the lytic activity of TKI. Suppression of SALL4
by siRNA partially abrogates a TKI-associated increase in ABCA3 ex-
pression and increases susceptibility of CML cells to cytotoxicity of
tyrosine kinase inhibition. Treatment with indomethacin inter-
rupts the inducible SALL4/ABCA3 pathway in CML cells to restore
TKI susceptibility.
Constitutive expression of SALL4 affects the sensitivity of endo-
metrial cancer cells to carboplatin treatment [35]. Overexpression
of SALL4 in carboplatin sensitive endometrial cancer cells could
further promote carboplatin resistance in a dose-dependent manner.
SALL4-transfected endometrial cancer cells show increased prolif-
eration after carboplatin treatment compared with control cells while
the overexpression also protects endometrial cancer cells from
carboplatin-induced apoptosis. In contrast, in carboplatin-resistant
endometrial cancer cells, SALL4 knockdown significantly sensi-
tizes the cells to carboplatin treatment. SALL4 directly regulates
c-Myc transcriptional activity in endometrial cancer cells, which may
be partially responsible for the chemotherapy resistance induced
by SALL4 upregulation. In addition, SALL4 expression is correlated
with chemosensitivity in liver cancer cells. SALL4-overexpression
induces survival and proliferation of liver cancer cells in response
to 5-FU treatment, suggesting that SALL4 expression results in se-
lection of chemoresistant cells [33].
SALL4 and epigenetic modulation
In addition to transcriptional control, SALL4 also regulates gene
expression through epigenetic mechanisms. DNA methylation,
histone modification, chromatin remodeling, and non-coding RNAs
are the four major molecular mechanisms responsible for epigen-
etic modification. Yang et al. suggest that SALL4 protein directly
interacts with DNA methyltransferases (DNMTs), indicating that
SALL4 is able to repress transcription through recruitment of DNA
methyltransferases [40]. In addition, SALL4 has been shown to co-
occupy target genes with polycomb repressive complex (PRC) [7].
SALL4 may repress gene transcription though the induction of PRC
components (such as Bmi-1) or interaction with PRC complex
members. Moreover, SALL4 interacts with histone lysine-specific
demethylase 1 (LSD1) to repress gene transcription in stem cells [41].
In addition to gene repression, SALL4 is capable of binding to the
histone methyltransferase MLL to activate HOXA9 gene expres-
sion [21], suggesting that SALL4-mediated methylation and
 X. Zhang et al./Cancer Letters 357 (2015) 55–62
Fig. 3. SALL4 and epigenetic machinery. SALL4 represses or activates gene transcription through the interaction with distinct epigenetic modifiers. SALL4 suppresses gene
transcription through recruitment of DNA methyltransferases (DNMT), Mi-2/nucleosome remodeling and deacetylase (NuRD) complex, polycomb repressive complex (PRC),
and histone demethylase (LSD1). SALL4 activates gene expression through recruitment of histone methyltransferase such as MLL (mixed-lineage leukemia).
demethylation in DNA and histone may distinctly regulate gene ex-
pression in stem cells and cancer. Second, SALL4 is associated with
Mi-2/nucleosome remodeling and deacetylase (NuRD) complex and
the SALL4-interacting protein complex exhibits histone deacetylase
(HDAC) activity [42]. For instance, SALL4 co-occupies the same pro-
moter regions of PTEN as HDAC2 and represses its expression in vitro,
indicating that SALL4-repressed gene transcription could be me-
diated by histone deacetylation and nucleosome remodeling.
However, there is a lack of studies about the regulatory effects of
SALL4 on non-coding RNA in epigenetic modulation. Therefore, the
existing data suggest that SALL4 may recruit multiple epigenetic
modifiers to synergistically remodel local chromatin structure and
coordinately regulate gene transcription (Fig. 3).
SALL4 regulation in cancer
SALL4 is regulated at multiple levels in cancer. Aberrant
hypomethylation of the promoter region of SALL4 gene is ob-
served in MDS patients and SALL4 mRNA level is highly associated
with the status of SALL4 hypomethylation, indicating that SALL4 gene
expression is dysregulated in MDS patients by epigenetic mecha-
nism [43]. The frequency of SALL4 hypomethylation is significantly
increased in higher risk MDS patients, suggesting that
hypomethylation of SALL4 gene is involved in the progression of
MDS. In addition, SALL4 gene is aberrantly hypomethylated in acute
myeloid leukemia patients and the status of SALL4 gene methyla-
tion is associated with intermediate and poor karyotypes of AML
[44]. SALL4 is also regulated by a variety of transcription factors that
are closely linked with tumor development and progression. Mul-
tiple STAT3-binding sites have been identified in the SALL4 gene
promoter region. Down-regulation of STAT3 activity remarkably de-
creased the expression of SALL4 [45]. STAT3-mediated SALL4
regulation is critical for the survival of breast cancer cells. SALL4
expression is also regulated by the canonical Wnt signaling pathway.
SALL4 promoter contains a conserved TCF/LEF-binding site. Co-
transfection of β-catenin with LEF1 (or TCF4E) greatly increases SALL4
luciferase activity while mutation of the TCF/LEF-binding site at-
tenuates SALL4 luciferase activity, suggesting that SALL4 is a direct
transcriptional target of canonical Wnt signaling [46]. Further-
more, SALL4 interacts with β-catenin to cooperatively activate its
target genes. Therefore, the regulation of SALL4 by Wnt signaling
may form a feedback loop to fine-tune the Wnt signaling pathway.
SALL4 is identified as a direct target of caudal-related homeobox
1 (CDX1) transcription factor [47]. SALL4 is aberrantly expressed in
the CDX1-positive intestinal metaplasia of the stomach in both
59
humans and mice. CDX1-induced SALL4 converts gastric epitheli-
al cells into tissue stem-like progenitor cells, which then
transdifferentiate into intestinal epithelial cells, suggesting that SALL4
is a critical component of CDX1-directed transcriptional circuitry
that promotes intestinal metaplasia. Furthermore, SALL4 is found
to be regulated by microRNA in glioma cells [48]. MiR-107 mimics
reduce while miR-107 inhibitors increase the SALL4 mRNA level.
MiR-107 overexpression inhibits cell proliferation and induces apop-
tosis in glioma cells, which are reversed by SALL4 reintroduction.
An obvious inverse correlation between miR-107 expression and
SALL4 level is observed in clinical glioma samples, indicating that
upregulation of miR-107 inhibits glioma cell growth through direct
targeting of SALL4. SALL4B can be modified by both ubiquitination
and sumoylation at the post-translational level. However, SALL4B
sumoylation is independent of ubiquitination while lysine resi-
dues 156, 316, 374, and 401 are essential for sumoylation. It is known
so far that only SALL4 sumoylation is functionally important [49].
A constitutive sumoylation of SALL4B is readily detectable in tera-
tocarcinoma cells. SUMO-deficiency compromises the trans-
activational or trans-repressional activities of SALL4B, suggesting
that sumoylation is an important post-translational modification for
SALL4 activity.
SALL4 as cancer biomarker and target
SALL4 seems to be a sensitive and specific cancer biomarker.
SALL4 expression is reported in numerous malignancies, such as pre-
cursor B-cell lymphoblastic lymphoma [50,51], myelodysplastic
syndromes [52], acute myeloid leukemia [11], chronic myeloid leu-
kemia [30], breast cancer [32], lung cancer [31,53], endometrial
cancer [35], liver cancer [33,38], gastrointestinal carcinoma
[34,54–56], glioma [48,57], germ cell tumors (GCTs), and yolk sac
tumors [58–60]. SALL4 expression correlates with disease progres-
sion in human AML and its expression in AML patients is correlated
with treatment status. Therefore, SALL4 may be used as a marker
for diagnosis and prognosis for AML. SALL4 is expressed at a high
level in the early clinical stages of breast cancer, indicating that SALL4
may be helpful for breast cancer screening. SALL4 expression is re-
activated in human HCC patients. HCC patients with high SALL4
expression are significantly associated with shorter survival. SALL4
is an independent prognostic factor for overall survival and early
recurrence of HCC. In endometrial cancer patients, the level of SALL4
expression is positively correlated with worse patient survival and
aggressive features such as metastasis. In colorectal carcinoma (CRC),
significant increase in SALL4 expression is detected in 87% of tumor
60 X. Zhang et al./Cancer Letters 357 (2015) 55–62
tissues and SALL4 expression is highly correlated with tumor me-
tastasis. In esophageal carcinoma (ESCC), SALL4 expression has a
significant correlation with invasion and metastasis of the disease
[61]. We have shown that SALL4 expression is up-regulated in gastric
cancer patients and high level of SALL4 predicts poor prognosis in
these patients. Furthermore, a high level of SALL4 protein is de-
tected in the serum of HCC patients [62]. HCC patients with high
SALL4 serum levels have poor prognosis evidenced by both tumor
recurrence and overall survival rate, suggesting that the high serum
level of SALL4 is a novel prognosis biomarker for HCC patients.
In addition to being a biomarker for cancer diagnostics, SALL4
may also constitute a possible therapeutic target. The inhibition of
SALL4 expression by siRNA causes reduced cell survival and im-
paired migration and invasion in distinct cancer cells in vitro. Stable
knockdown of SALL4 by shRNA efficiently retards tumor growth and
restrains tumor metastasis in animal models. Moreover, SALL4 si-
lencing by miRNA inhibits glioma cell proliferation and induces
apoptosis in vitro and in vivo. These findings suggest that deple-
tion of SALL4 has potential anti-tumor effects. In addition, natural
compounds such as matrine and apigenin have been shown to sup-
press SALL4 expression and inactivate the β-catenin signaling
pathway in leukemic cells [63]. However, the specificity of these
natural compounds to SALL4 still needs to be further investigated.
SALL4 also serves as an ideal target for combined therapy. SALL4
knockdown in combination with Bcl2 inhibitor treatment in-
creases the apoptotic AML cells to 2–3 folds compared to cells treated
alone [64], suggesting that the combination of Bcl2 inhibitor and
down-regulation of SALL4 could be a novel therapeutic strategy in
treating AML patients. In human hepatocellular carcinoma, HDAC
inhibitor SBHA reduces SALL4 expression and inhibits the prolif-
eration of SALL4-positive HCC cells, suggesting the therapeutic
potential of these inhibitors in the treatment of SALL4-positive HpSC-
HCC through targeting SALL4 [38]. Furthermore, interfering with the
interaction of SALL4 and its epigenetic partner complex has ther-
apeutic effects in cancer. Gao and colleagues have developed a
peptide inhibitor that can compete with SALL4 in interacting with
the HDAC complex [65]. They demonstrate that treating SALL4-
expressing leukemic cells with this peptide leads to cell death
through the reactivation of PTEN. The antileukemic effect of this
peptide can be confirmed on primary human leukemia cells in
culture and in vivo, and is identical to that of down-regulation of
SALL4 in these cells by using siRNA. The biological activity of this
peptide is further confirmed in hepatocellular carcinoma. The SALL4
peptide inhibitor inhibits the viability of SALL4-overexpressing he-
patocellular carcinoma cells in a PTEN-dependent manner, with
minimal toxic effects on SALL4-negative cells, as compared with the
HDAC inhibitor trichostatin (TSA). To test the therapeutic effect of
this peptide for in vivo treatment, the peptide is conjugated with
the transactivator of transcription (TAT) protein transduction domain
and intraperitoneally injected into NOD/SCID mice bearing subcu-
taneous xenograft tumor [66]. TAT fusion peptide greatly reduces
the tumorigenicity of SALL4-overexpressing hepatocellular carci-
noma cells, suggesting that the SALL4 peptide inhibitor is a potent
anti-cancer agent for SALL4-overexpressing hepatocellular
carcinoma.
Conclusions and future directions
Over the past decade, accumulating evidence indicates that SALL4
plays a key role in cancer biology in addition to its seminal func-
tion in stem cells and development. In distinct types of cancer, SALL4
has been shown to be crucial for cell survival and proliferation, in-
vasive migration, and chemoresistance. Evidence from mouse models
suggests that SALL4 is critically involved in leukemogenesis. SALL4
protein may either function as a transcription activator or suppres-
sor to regulate the expression of downstream target genes. However,
the pathological roles of SALL4 in cancer seem to be dependent on
cell type and context. Therefore, it is necessary to establish mouse
models in which SALL4 isoforms are conditionally activated or
knocked down in certain cell types. In addition, the oncogenic func-
tions of SALL4 have not been completely characterized. Much less
is known about the roles of SALL4 in the other hallmarks of cancer
such as sustained angiogenesis, immune evasion, and deregulated
energy metabolism. The underlying molecular mechanisms respon-
sible for the different functions of SALL4 in tumor development and
progression have not been fully elucidated. Up to now only a few
mediators have been identified, it is conceivable that many other
downstream targets of the SALL4 signaling pathway remain to be
discovered. Thus, transcriptomic and proteomic analyses to reveal
the global downstream target genes (including both coding and non-
coding genes) and interacting proteins for SALL4 will help establish
the integrated signaling network in cancer. Moreover, the mecha-
nisms driving the re-activation of SALL4 in cancer remain largely
unknown. The activation of SALL4 upstream regulators is fre-
quently seen in human cancers. For instance, STAT3 is associated
with constitutive SALL4 expression in breast cancer and inhibition
of STAT3 activity disrupts SALL4 expression [58]. Thus, we need to
understand if any other genetic or epigenetic modifications of SALL4
gene exist that contribute to tumor development and progression.
In addition, a specific peptide inhibitor for SALL4 has shown
promising anti-cancer activity and further efforts to develop small-
molecule peptide mimetics or combine with conventional anti-
cancer drugs may help rediscover its therapeutic value. Targeted
delivery of siRNA and other inhibitors to disrupt the expression and
function of SALL4 in cancer cells by using advanced biotechnolo-
gies will provide a new strategy for cancer therapy. Finally, SALL4
is known to maintain the self-renewal and pluripotency of stem cells,
it is interesting to test whether targeting SALL4 will be able to erad-
icate CSCs given that CSCs are thought to cause metastasis,
chemoresistance, and subsequently tumor recurrence. Answers to
these important questions will shed light on the role of SALL4 in
cancer biology and provide full potential for SALL4 as a valid cancer
biomarker and target.
Acknowledgements
This work was supported by the Major Research Plan of the Na-
tional Natural Science Foundation of China (Grant No. 91129718),
the National Natural Science Foundation of China (Grant No.
81201660), the Natural Science Foundation of the Jiangsu Prov-
ince (Grants No. BK2012709 and BK20141303), Jiangsu Province’s
Project of Scientific and Technological Innovation and Achieve-
ments Transformation (Grant No. BL2012055), Jiangsu Province’s
Outstanding Medical Academic Leader and Sci-tech Innovation Team
Program (Grant No. LJ201117), Jiangsu Province’s Qing Lan project,
Foundation for Young Academic Leader of Jiangsu University, Start-
ing Foundation for Senior Talents of Jiangsu University (Grant No.
13JDG086).
Conflict of interest
No conflict of interest to be declared.
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