Introduction

Basic helix-loop-helix (bHLH) transcription factors are crucial determinants that regulate lineage- and developmental-specific gene networks [1]. They are characterized by specific protein structures, such as the basic and HLH domains. The basic domain mediates their direct binding with DNA, whereas the HLH domain is involved in dimerization [2]. Currently, more than 240 bHLH family members have been identified in species ranging from yeast to human [3]. They are grouped into seven distinct classes (I to VII) according to their expression patterns, dimerization selectivity, and DNA-binding specificity [1]. bHLH proteins act as important regulators in a wide spectrum of biological processes through controlling the expression of many genes involved in proliferation [4], apoptosis [5], differentiation [6], autophagy [7], cell cycle [8], cell growth [9], development [10], angiogenesis [11], hematopoiesis [12], morphogenesis [13], and tumorigenesis [14]. Therefore, they play crucial roles in human health and disease, particularly cancer.

Transcription factor 21 (TCF21), also known as capsulin, epicardin, or Pod1, is a member of the class II bHLH transcription factor superfamily and is widely expressed in multiple tissues and organs [15,16,17]. It was first cloned in 1998 from various tissues and organs by five different laboratories simultaneously [15,16,17,18,19]. TCF21 has been shown to play crucial roles in organogenesis and the regulation of numerous cellular functions [20,21,22,23,24,25,26,27]. Loss of TCF21 results in abnormalities in multiple organs, as well as neonatal lethality [28, 29]. Its expression and activity are regulated by different mechanisms, such as non-coding RNAs (ncRNAs) [30], post-translational modifications (PTMs) [31], and protein–protein interactions [32]. A large number of studies have demonstrated that dysregulation of TCF21 has been correlated with many diseases, including cancer [23, 33,34,35,36]. This review focuses on the exact regulation mechanisms of TCF21, and on recent findings regarding its vital functions in health and cancer, presents important advances in the potential use of TCF21 as a biomarker in cancer therapy, and discusses future directions of research aimed at developing applications of TCF21 as a target for cancer treatment.

Overview: structure and functions of TCF21

Structure of TCF21

The TCF21 gene is located in the human chromosome 6q23-q24, and encodes an estimated 20 kDa functional TCF21 protein composed of 179 amino acids. Its structure is highly conserved across species. The bHLH domain of TCF21 mainly mediates its dimerization and direct interaction with DNA. It also contains an N-terminal interface domain (amino acids 2 to 100), which mediates its interaction with mitogen-activated protein kinase 1 (MEK1) [37]. Both the bHLH and the C-terminal domains (amino acids 80 to 179) of TCF21 are required to mediate the interaction between TCF21 and HeLa E-box-binding protein (HEB) [38]. Moreover, the N-terminal portions (amino acids 1 to 77) are required for the interaction of TCF21 with androgen receptor (AR) [39] (Fig. 1).

Fig. 1
figure 1

Schematic diagram of the TCF21 structure. Letters within the bar represent structural domains. The well-known proteins that interact with TCF21 are shown above the lines in the corresponding domains. Only representatives of TCF21-interacting proteins are shown. bHLH, basic helix-loop-helix DNA–binding domain; AR, androgen receptor; HEB, HeLa E-box-binding protein; MEK, mitogen-activated protein kinase

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Functions of TCF21

TCF21 is a key bHLH transcription factor that regulates cell fate and differentiation during the development of various tissues and organs, such as muscle [40,41,42], gonads [43], testes [24, 39, 44], and spleen [45]. It is also strongly associated with organogenesis [28]. Besides, TCF21 mediates multiple physiological and pathological processes by targeting signaling pathways or inducing the expression of target genes involved in angiogenesis [46], endometriosis [36], epithelial–mesenchymal transition (EMT) [22], cell cycle [47], and autophagy [34]. It is also involved in the regulation of proinflammatory environment and active extracellular matrix (ECM) remodeling of visceral and subcutaneous fat pads [48]. In addition, TCF21 plays an important role in sex determination and differentiation [27, 49]. The multiple functions of TCF21 in biological processes indicate that its dysregulation is closely correlated with a number of diseases, particularly cancer. Therefore, further studies are required to explore its physiological functions and clinical applications.

Molecular mechanisms of TCF21 regulation

The expression and activity of TCF21 are regulated by distinct mechanisms, such as DNA methylation, ncRNAs, and PTMs. Here, we summarize the main modes of TCF21 regulation in physiological and pathological conditions.

Regulation of TCF21 at the transcription level

DNA methylation plays important roles in regulating numerous biological processes, such as development, aging, and tumorigenesis [50]. Aberrant DNA methylation is closely correlated with the occurrence and development of malignant tumors. Hypermethylation inhibits the expression of genes at the transcriptional level [51], whereas hypomethylation mainly influences chromosome stability and improves aneuploidy [52]. TCF21 promoter hypermethylation has been found in a variety of cancers, including head and neck [53, 54], lung [55,56,57], colon [58], kidney [59,60,61], breast [55], gastric [62], and urological [63] cancer. Correspondingly, low expression of TCF21 is observed in these malignant tumors. In addition to solid tumor tissues, aberrant TCF21 methylation has also been detected in sputum and urine specimens from patients with cancer [55, 59]. Gooskens et al. demonstrated that hypermethylation of TCF21 promoter silences its expression, whereas TCF21 overexpression suppresses clonogenic proliferation and migration of renal tumor cells [60]. Moreover, TCF21 hypermethylation is significantly associated with lymph node invasion in colon cancer patients [58]. These studies suggest that the detection of TCF21 methylation status has the potential to be used in clinical applications.

p53 is a well-studied transcription factor that acts as a tumor suppressor in malignant diseases, and its gene is known to be frequently mutated in human cancers [64,65,66]. Li et al. showed that TCF21 is a direct target gene of p53. Its expression in p53-positive cells is significantly increased compared with that in p53-negative cells. They also showed that TCF21 promoter contains four potential p53-binding motifs. p53 binds to the TCF21 promoter and promotes its expression to respond to hypoxic stress [37]. Sex-determining region Y (SRY) is a key regulator of male sex determination, acting as a master switch that regulates the testis determination pathway [67]. Bhandari et al. revealed that overexpression of SRY increases the transcription activity of the TCF21 promoter. They also found that SRY directly binds to the SRY/SOX9 response elements in the TCF21 promoter and activate its expression during fetal rat testis development. A mutation of SRY/SOX9 response elements leads to the loss of SRY actions on TCF21 promoter [44]. In addition, analysis of DNA sequence showed that the TCF21 promoter also possesses other transcription factor binding motifs, such as SOX9 and GATA4, indicating the potential regulation of TCF21 expression by other transcription factors [44].

Post-transcriptional regulation of TCF21 by non-coding RNAs

Non-coding RNAs (ncRNAs) are crucial factors that play an important role in regulating gene expression and chromatin structure [68]. They are divided into different classes according to their specific biogenesis and function, including long non-coding RNA (lncRNA), piwi-interacting RNA (piRNA), microRNA (miRNA), small interfering RNA (siRNA), small nuclear RNA (snRNA), and circular RNA (circRNA) [50, 69]. In recent years, growing studies show that ncRNAs contribute to the post-transcriptional regulation of TCF21 (Table 1).

Table 1 ncRNAs targeting TCF21 in cancer
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MicroRNAs are small non-coding RNAs that regulate the expression of genes involved in many crucial physiological and pathological processes [74,75,76]. They target the 3′-untranslated region (3′UTR) of gene messenger RNAs (mRNAs) to repress these genes translation [77]. TCF21 is a direct target of miR-224 and miR-146a in coronary heart disease. miR-224 binds to the TCF21 3′UTR C variant, and inhibits TCF21 expression at the transcription level in human coronary artery smooth muscle cells [78]. miR-146a directly binds to TCF21 promoter. However, rs2910164 in miR-146a disrupts its binding to TCF21 promoter and increases the risk of coronary heart disease in an Iranian population [79]. TCF21 is also regulated by several miRNAs in cancer, including miR-205, miR-92a, miR-3648, miR21, and miR-1228. miR-205 promotes invasion of ovarian cancer cells by directly targeting TCF21. Consistent with this, miR-205 expression is negatively correlated with TCF21 expression in patients with ovarian cancer [70]. TCF21 is also a potential target of miR-92a in osteosarcoma cells. Overexpression of miR-92a promotes proliferation, invasion, growth, and metastasis of osteosarcoma cells by inhibiting TCF21 expression [73]. Moreover, miR-3648 promotes invasion and metastasis of human bladder cancer by negatively regulating TCF21 [80]. In renal cancer, miR-21 overexpression promotes invasion of renal cell carcinoma Caki-1 cells by directly targeting TCF21 [72]. Similar to miR-205, a negative correlation is observed between expression of miR-1228 and TCF21 in lung cancer samples. miR-1228 directly interacts with TCF21 mRNA and inhibits TCF21 expression in lung cancer cells [71].

Circular RNAs are a class of endogenous non-coding RNAs characterized by a stable cyclic structure [81]. Growing evidence shows that circRNAs play a crucial role in human health and diseases, particularly in cancer [82,83,84]. It is well defined that circRNAs regulate gene expression by sponging miRNAs [85,86,87]. TCF21 is an indirect target of circRNAs. For example, overexpression of hsa_circ_100395 inhibits proliferation, migration, and invasion of lung cancer cells through upregulation of TCF21 by sponging miR-1228, indicating a novel regulatory loop of hsa_circ_100395/miR-1228/TCF21 axis in lung carcinogenesis [71].

Long non-coding RNAs are a class of important regulators more than 200 nucleotides in length, which participate in a number of cellular functions and disease processes [88, 89]. They act as endogenous miRNA sponges to regulate gene expression involved in carcinogenesis [90,91,92]. They can also alter epigenetic signatures through interactions with chromatin remodeling enzymes [93,94,95]. TCF21 can be regulated by lncRNAs. For instance, lncRNA TCF21 antisense RNA inducing demethylation (TARID) promotes TCF21 expression through inducing promoter demethylation. This process is mediated by growth arrest and DNA damage-inducible protein 45 alpha (GADD45A), a crucial regulator of DNA demethylation. TARID interacts with GADD45A and then recruits thymine-DNA glycosylase to promote demethylation of the TCF21 promoter, leading to upregulation of TCF21 [30]. TCF21 is also a target of lncRNA LINC00163 in lung cancer cells. LINC00163 overexpression significantly inhibits proliferation, migration, and invasion of lung cancer cells in vitro and impairs tumor propagation in vivo through upregulation of TCF21 [96]. These studies reveal a complex network of ncRNAs in TCF21 regulation, which are involved in TCF21-related disease progression, including cancer. Further studies are required to fully understand the relation of ncRNAs to TCF21 for TCF21-based treatment strategies.

Post-translational modifications contribute to TCF21 regulation

PTMs are dynamic reversible processes that play crucial roles in regulating protein functions, such as protein stability, subcellular translocation, DNA-binding affinity, protein folding, and interaction with other proteins [50]. Common PTMs in mammalian include phosphorylation, sumoylation, ubiquitination, methylation, succinylation, and acetylation [77, 97, 98].

Growing evidence suggests that TCF21 is regulated by PTMs, including phosphorylation, ubiquitination, and sumoylation (Fig. 2). Phosphorylation is a well-studied PTM that plays an important role in regulating a variety of cellular functions, such as cell growth, proliferation, apoptosis, and cell cycle [99, 100]. A large number of transcription factors, such as forkhead box protein K2 (FOXK2), forkhead box protein O3a (FOXO3a), and p53, have been shown to be regulated by phosphorylation [101,102,103]. TCF21 is a target of phosphorylation. Mass spectrometry analysis revealed that three phosphorylation sites (serine residues S37, S48, and S67) exist in TCF21 amino acid sequence (Fig. 1). These phosphorylation sites are localized in the N-terminal region of TCF21 structure and are evolutionarily conserved across species, indicating the functional role of TCF21 phosphorylation in the specification and maturation of proepicardial cells [31]. Sumoylation is a crucial post-translational modification involved in regulation of protein functions, such as protein subcellular translocation, protein half-life, and interaction between proteins [104]. Our previous study demonstrated that TCF21 can be sumoylated by small ubiquitin-like modifier 1 (SUMO1) at lysine residue 24, and SUMO-specific protease 1 (SENP1) mediates its desumoylation. The study further showed that sumoylation can extend the half-life of TCF21 but cannot change its subcellular localization. It also found that TCF21 sumoylation enhances its inhibition on the transcriptional activity of estrogen receptor-α (ERα) by recruiting histone deacetylases 1/2 (HDAC1/2), leading to the suppression of ERα-positive breast cancer cell growth [105]. PTMs have been reported to interact with each other, thus exploring the PTMs network of TCF21 is crucial to understanding the mechanisms of TCF21 regulation.

Fig. 2
figure 2

Regulation of TCF21 by post-translational modifications (PTMs). TCF21 is sumoylated by the small ubiquitin-like modifier 1 (SUMO1). Sumoylation of TCF21 inhibits the transcriptional activity of estrogen receptor-α (ERα) by recruiting histone deacetylases 1/2 (HDAC1/2). SUMO-specific protease 1 (SENP1) mediates the desumoylation of TCF21. Mutation of TCF21sumoylation site enhances the ubiquitination of TCF21, leading to its degradation in a ubiquitin/proteasome-dependent manner

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Implication of TCF21 in disease development

The role of TCF21 in non-neoplastic diseases

TCF21 is shown to be associated with several cardiovascular diseases, such as coronary artery disease (CAD), ventricular septal defects, and hypertension. It has been reported that TCF21 inhibits differentiation of human coronary artery smooth muscle cells and decreases CAD risk [106]. It specifically binds to the conserved sequence CAGCTG in target genes and regulates a network of genes associated with CAD [107]. TCF21 also mediates the regulation of disease-related growth factor and embryonic signaling pathways on CAD risk [35]. In addition, TCF21 rs12190287 is reported to increase the susceptibility to CAD in an Iranian population [79]. rs12190287 has also been found to increase the susceptibility to hypertension [108] and ventricular septal defects [109].

TCF21 is also linked with the development of endometriosis and proteinuric renal disease. Endometriosis affects 10–15% of women of reproductive age [110]. TCF21 expression is found to be significantly increased in endometriotic stromal cells compared with that in endometrial stromal cells. Knockdown of TCF21 in endometriotic xenografts results in the abrogation of ectopic lesion growth in mice [36], indicating the potential of TCF21 as a target for endometriosis treatment. Podocytes are central components of glomerular filtration barrier [111]. Defects of podocyte differentiation cause glomerular injury, leading to proteinuria and glomerulosclerosis [112]. TCF21 is shown to highly express in podocytes. Knockdown of TCF21 in podocytes leads to glomerular abnormality with a decreased number of endothelial and mesangial cells. Moreover, 40% of 5-week-old podocyte-specific TCF21 knockout mice develop massive proteinuria and similar lesions with focal segmental glomerulosclerosis [33].

The role of TCF21 in carcinogenesis

It is well-known that TCF21 plays an important role in regulating cellular functions, including proliferation, differentiation, epithelial–mesenchymal transition, invasion, metastasis, cell cycle, autophagy, and survival. Thus, its dysregulation is closely related to a number of cancers (Table 2). A deeper understanding of TCF21 mechanisms in carcinogenesis will contribute to better diagnosis and treatment of cancer.

Table 2 Functional roles of TCF21 in different types of cancer
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TCF21 targets signaling pathways in cancer

Growing evidence shows that TCF21 is involved in the regulation of signaling pathways in cancer. Understanding its mechanism in signaling pathway regulation may provide us new insights into cancer progression. PI3K/AKT signaling pathway modulates a variety of cellular functions during cancer progression, such as cell proliferation, metastasis, and drug resistance [123]. It has been reported that overexpression of TCF21 significantly downregulates the expression of PI3K and p-AKT in human colorectal cancer cell lines [118]. Another study showed that knockdown of TCF21 increases p-AKT expression, whereas overexpression of TCF21 decreases p-AKT expression in gastric cancer cell lines. In gastric cells treated with LY294002 (AKT inhibitor), knockdown of TCF21 failed to reduce CDDP-induced apoptosis [20]. In addition, overexpression of TCF21 is shown to significantly decrease the expression of p-PI3K and p-AKT in cholangiocarcinoma cells. Administration of 740 Y-P (PI3K activator) significantly recovered p-PI3K, and p-Akt levels suppressed by TCF21 in cholangiocarcinoma cells [46]. These studies suggest that TCF21 may act as a tumor suppressor by targeting PI3K/AKT signaling pathway.

Mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway plays a crucial role in regulating fundamental cellular processes, such as cell proliferation, differentiation, migration, senescence, and apoptosis. Dysregulation of MAPK/ERK cascade is closely associated with many aspects of carcinogenesis [124, 125]. In cholangiocarcinoma cells, overexpression of TCF21 is shown to significantly downregulate the expression of p-ERK1/2, without affecting the total protein expression [46]. In another study, overexpression of TCF21 significantly reduces the expression of p-ERK1/2 in uterine corpus endometrial carcinoma cells. They also found that TCF21 directly interacts with MEK1 through its N-terminal interface domain (2–100) and inhibits the kinase activity of MEK1 by blocking the key functional domain of MEK1, leading to downregulation of p-ERK1/2 level [37]. These studies indicate that TCF21 suppresses cancer progression by inhibiting MAPK Pathway.

Estrogen receptor signaling pathway mediates estrogen-stimulated proliferation, migration, and survival of target cells. This pathway is the target of hormone therapy for ER-positive breast cancer [126]. In previous study, we found that TCF21 suppresses the growth of ERα-positive breast cancer cells by targeting estrogen receptor signaling pathway. TCF21 directly interacts with ERα, and inhibits its transcriptional activity in a HDACs-dependent manner [105]. Taken together, these studies suggest that TCF21 may be a core factor in the network of signaling regulation in cancer progression.

TCF21 regulates proliferation, apoptosis, and cell cycle

The main characteristics of cancer cells are their persistent proliferation and evasion of apoptosis [127]. A growing number of studies show that TCF21 plays an important role in carcinogenesis as a tumor suppressor (Fig. 3). Consistent with this, the expression of TCF21 has been shown to be significantly decreased in tumor tissues compared with that in adjacent normal tissues [22, 61, 113]. It has been reported that the anti-tumoral functions of TCF21 are closely related to inhibiting proliferation and promoting apoptosis in various types of cancer, such as colorectal [58], gastric [20], lung [34], breast [113], and liver cancer [128], as well as esophageal squamous cell carcinoma [22] and uterine corpus endometrial carcinoma [37].

Fig. 3
figure 3

The role of TCF21 in cancer progression. TCF21 mainly acts as a tumor suppressor by inhibiting proliferation, cell cycle, epithelial–mesenchymal transition (EMT), invasion, metastasis, autophagy, and angiogenesis, and by inducing apoptosis in various types of cancer

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The anti-tumoral characteristics of TCF21 may be partly due to its negative regulation on cell cycle progression. Cyclin D1 is a crucial intracellular mediator of extracellular signals that control proliferation, and is involved in regulation of the cell cycle and pathological process [129]. In our previous work, we found that TCF21 significantly inhibits the transcriptional activity of cyclin D1 in ERα-positive breast cancer cell lines MCF-7 and ZR-75-30, and that overexpression of TCF21 results in cell cycle arrest of MCF-7. Furthermore, TCF21 directly interacts with ERα and inhibits its transcriptional activity, leading to the suppression of MCF-7 cell proliferation [105]. Cyclin E1 is another key regulator in cell cycle progression due to its role in inducing S phase entry [130]. Franca et al. showed that TCF21 overexpression significantly increases cyclin E1 expression through targeting SHP in hepatocarcinoma cell line HepG2 [117]. Moreover, TCF21 overexpression inhibits the transition of gastric cancer cells from G1 to S phase [20]. These findings indicate the crucial regulatory role of TCF21 in cell cycle balance.

In addition, TCF21 represses proliferation of uterine endothelium tumor cells through inhibiting MAPK signaling pathway [37]. Molecular studies on colorectal and gastric cancer cells revealed that TCF21 overexpression inhibits proliferation of tumor cells by repressing PI3K/AKT signaling pathway [20, 118]. These studies indicate that TCF21 exerts its anti-tumoral effect in different cancers through diverse mechanisms. Further studies are needed to investigate the exact mechanism of TCF21 in carcinogenesis, which may provide new insights for the TCF21-based therapeutics strategy in cancer.

TCF21 in tumor angiogenesis

Abnormal angiogenesis is shown to be responsible for multiple pathological processes, including carcinogenesis [131, 132]. Tumor angiogenesis contributes to tumor growth by supplying oxygen and nutrients to cancer cells, while its suppression results in tumor stasis [133]. It has been reported that tumors lacking of TCF21 in nude mice are more vascular than tumors that expressed wild-type TCF21, indicating the potential inhibitory role of TCF21 on tumor angiogenesis [53]. Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) are crucial pro-angiogenic factors that maintain the angiogenic phenotype of vessel cells, which contribute to carcinogenesis [134]. Duan et al. demonstrated that overexpression of TCF21 significantly inhibits angiogenesis in cholangiocarcinoma xenograft tumors, and targets the expression and secretion of VEGF and PDGF in vitro and in vivo. The suppression of VEGF and PDGF production by TCF21, in turn, reduces proliferation, invasiveness, and tube formation of endothelial cells. The study also showed that TCF21 exerts its anti-angiogenic influence by targeting PI3K/AKT and ERK1/2 signaling pathways in cholangiocarcinoma [46]. Despite the progress that has been made in investigating the influence of TCF21 on tumor angiogenesis, further studies are needed to elucidate its exact mechanism, which leads to the development of novel TCF21-based anti-angiogenesis therapeutics.

TCF21 and autophagy

Growing studies suggest that autophagy is closely associated with the development of many diseases, including cancer [135]. Autophagy is a double-edged sword in cancer progression. Normally, it can induce cell death by activating apoptosis signaling pathways. However, an increasing number of studies show that autophagy also promotes cancer cell survival during treatment [136]. For instance, a correlation between TCF21 expression and autophagy is observed in lung cancer progression. TCF21 knockdown may promote global DNA methylation of non-small cell lung cancer cells, leading to increased autophagy. This process contributes to lung cancer progression. In turn, autophagy inhibition by 3-methyladenine (3-MA), an autophagy inhibitor, significantly promotes TCF21 promoter methylation, leading to upregulation of TCF21 expression and enhanced apoptosis [34]. Research on the role of TCF21 in regulating autophagy is currently limited. Further studies are thus required to elucidate its exact mechanisms.

The role of TCF21 in EMT

EMT plays a crucial role in many physiological processes, such as embryonic development, mesoderm formation, and tissue repair. Aberrant activation of EMT contributes pathologically to a number of diseases, including cancer [50, 137, 138]. During the EMT process, the expression of epithelial markers is decreased, whereas the expression of mesenchymal markers is increased [50].

TCF21 has been shown to correlate with EMT in a number of cancer types. For instance, TCF21 expression is essential in maintaining the epithelial phenotype of cells. Overexpression of TCF21 results in increased expression of epithelial markers WNT4 and CDH1, and decreased expression of mesenchymal markers SNAI1 and vimentin in lung cancer cell line A549 [53]. Moreover, high expression of WNT4 is also observed in TCF21-positive lung cancer cells [55], indicating that WNT4 may be one of the targets of TCF21. Cancer stem cells (CSCs) are generated during EMT progress, which are recognized as the main cause of therapeutic resistance, metastasis, and recurrence of cancer [115, 139]. Upregulation of TCF21 induced by curcumin is shown to inhibit the emergence of CSCs in lung cancer. In breast cancer cell line MDA-MB-231, ectopic TCF21 expression significantly decreases SNAI1 expression, and inhibits the EMT [113]. Furthermore, TCF21 overexpression in colorectal cancer cells significantly downregulates the expression of mesenchymal marker vimentin and upregulates the expression of epithelial marker E-cadherin [58], indicating its inhibitory role in the EMT of colorectal cancer. However, overexpression of TCF21 in renal cancer cells significantly upregulates the expression of epithelial marker E-cadherin at both the mRNA and the protein levels, but does not affect the mRNA level of vimentin and SNAI1 [60]. Taken together, these studies confirm the involvement of TCF21 in regulating EMT progress by controlling the expression of EMT-related genes such as WNT4, CDH1, vimentin, SNAI1, and E-cadherin.

TCF21 controls invasion and metastasis

Invasion and metastasis are the most life-threatening aspects of cancer progression [140]. Metastasis is a multistep pathological process characterized by the transfer of cancer cells from one primary site to other organs or tissues, while invasion is the first step toward metastasis and one of the major features of cancer [141, 142]. TCF21 has been identified as a key regulator of invasion and metastasis in a variety of cancer types. For instance, TCF21 expression or its SNPs have been shown to be closely associated with metastasis in some cancers, such as breast cancer [113], osteosarcoma [48], and hepatocellular carcinoma [143]. Overexpression of TCF21 is reported to inhibit invasion and metastasis in a number of cancers, including esophageal squamous cell carcinoma [22], uterine corpus endometrial carcinoma [37], melanoma [23], as well as ovarian [70], bladder [80], gastric [20], lung [34], and colorectal cancer [58, 118]. Chen et al. demonstrated that overexpression of TCF21 significantly upregulates Kiss-1 level and reverses EMT-related proteins (E-cadherin, N-cadherin, snail, twist, and vimentin), leading to inhibition of invasion and metastasis in esophageal squamous cell carcinoma [22]. Similarly, TCF21 also suppresses invasion and metastasis in bladder cancer [80] and metastatic melanoma by targeting Kiss-1 [23]. In addition, TCF21 overexpression inhibits migration and invasion of colorectal cancer cells through the inhibition of PI3K/AKT signaling and matrix metalloproteinase 2 (MMP2) and MMP9 expression [118]. TCF21 also represses invasion of ovarian cancer cells by downregulation of MMP2 and MMP10 [70]. Although progress has been made in exploring the regulatory mechanisms of invasion and metastasis, many aspects still need to be clarified.

TCF21 has been shown to play a crucial role in mediating the response of cancer cells to oxidative stress and hypoxia [37, 144]. Thioredoxin reductase 1 (TXNRD1) is an oxidoreductase that maintains reactive oxygen species and superoxide concentration. It has been reported that oxidative stress induced by H2O2 increases miR526b/miR655 expression in breast cancer cell line MCF-7. Upregulation of miR526b/miR655 increases TXNRD1 expression by targeting TCF21 [144]. Moreover, TCF21 is a hypoxia-driven p53 target and responds to hypoxia stress by inhibiting MAPK signaling pathway in uterine corpus endometrial carcinoma [37].

TCF21 as a biomarker and therapeutic target in cancer

Although, in recent years, many advances in the strategies of cancer diagnosis and treatment have been made, the incidence and mortality of cancer are still increasing, causing tremendous pain and heavy financial burdens to patients and their families. A large number of cancer patients still diagnosed in advanced stages due to the difficulty of observing early clinical symptoms. The identification of valuable biomarkers is very important for early screening and prognostic judgments of cancer treatments. A growing number of studies indicate that TCF21 is a promising candidate biomarker for the diagnosis, prognosis, and treatment of many types of cancer. For instance, the methylation pattern of the TCF21 promoter offers a sensitive diagnostic biomarker for several types of cancer, including colorectal [58], gastric [54], and lung [56, 57] cancer, as well as neck squamous cell carcinoma [54], metastatic melanoma [23], and urological cancers [59, 63]. In addition, low expression of TCF21 has been shown to correlate with poor prognosis in colorectal cancer [118], lung adenocarcinoma [116], clear cell renal cell carcinoma [119], hepatocellular carcinoma [143], esophageal squamous cell carcinoma [22], and lung cancer [115]. However, low expression of TCF21 is identified as an independent biomarker for favorable overall disease-specific survival in patients with head neck squamous cell carcinoma [120]. The opposite results may suggest that the prognostic values of TCF21 expression are diverse in different types of cancer. The clinical significance of TCF21 as a candidate biomarker has been validated by many small-scale studies. However, large-scale studies are still required to confirm possible clinical applications of TCF21 as a biomarker during cancer treatment.

Owing to its essential role in cancer progression, TCF21 has the potential to be an efficient therapeutic target. TCF21 overexpression has been reported to inhibit proliferation, migration, invasion, and metastasis in a variety of cancers [20, 58, 70, 143], which is indicative of its therapeutic value. Ectopic TCF21 expression also suppresses the EMT in lung, breast, renal, and colorectal cancer [53, 58, 60, 113]. Therefore, screening of natural products for drug discovery and synthesis of chemotherapeutic drugs targeting TCF21 may provide valuable and efficient therapeutic strategies for cancer treatment. In addition, as TCF21 has been shown to be a direct target of some miRNAs, circRNAs, and lncRNAs [30, 70, 71], screening or synthesis of novel drugs targeting these ncRNAs may also contribute to valuable therapeutic strategies. Although available data confirm the potential clinical applications of TCF21, further studies are needed to elucidate its mechanisms and effects in chemotherapy sensitivity and resistance.

Conclusions and perspectives

TCF21 is recognized as a key regulator in many crucial biological processes, including cell proliferation, differentiation, survival, cell cycle, EMT, invasion, metastasis, autophagy, specification, and maturation of cells as well as organogenesis. This may depend on its following characteristics: Firstly, TCF21 acts as a transcription factor to regulate the expression of its target genes involved in these progresses. Secondly, TCF21 targets crucial signaling pathways, such as PI3K/AKT, MAPK, and miRNAs. It may also cross talk with other signaling pathways. Thirdly, it regulates cellular functions by cooperating with other regulators, such as JUN, SMAD3, and HDAC1/2. Therefore, a controllable regulation of TCF21 expression and activity provides a balanced transcriptional network that guarantees proper growth and maturation during embryogenesis and organ development. Conversely, the dysregulation of TCF21 function contributes to the occurrence of a number of diseases, including cancer. Owing to its central role in transcriptional regulation, it has great potential as a therapeutic target for a number of cancers. For instance, ERα is a well-known efficient target of endocrine therapy in breast cancer. Our previous work demonstrated that TCF21 significantly inhibits the transcriptional activity of ERα in an HDAC-dependent manner in breast cancer [105], indicating its essential role in determining the sensitivity or resistance of endocrine treatment. As TCF21 is an effective tumor suppressor, its regulation by agonists both in normal and disease conditions may be useful in both preventing and treating a wide variety of cancers. Therefore, the identification of specific efficient TCF21 agonists could be a promising strategy for cancer treatment. In addition, as ncRNAs have been shown to be important regulators of TCF21, targeting the ncRNA-TCF21 axis may provide a new strategy for cancer treatment. Considering the complexity of the TCF21 network and its cross talk with other transcription factors, continued in-depth investigation of its role in health and in cancer is vital for providing novel TCF21-based therapeutic strategies for cancer patients. Nevertheless, targeting TCF21 can be a double-edged sword because of its key role in the development of normal tissues and organs, which may also affect carcinogenesis. The current challenge is to regulate TCF21 expression and activity in particular pathological conditions, which will need exact information on the regulation and activity of TCF21 in health and in cancer.