The expression of metastasis associated protein 2 in normal development and cancers: mechanism and clinical significance

The function of MTA2 in immune cells

Mta2 null mice exhibits partial embryonic lethality, while the surviving mice develop lupus-like autoimmune symptoms. Mta2 null T lymphocytes show hyperproliferation upon stimulation, which correlates with hyper-induction of interleukin (IL)-2, IL-4 and interferon (IFN)-γ (Lu et al., 2008). During mice preimplantation development, Mta2 is the only zygotically expressed Mta gene prior to the blastocyst stage. Knockdown of Mta2 leads to biallelic H19 expression and loss of DNA methylation on the imprinting control region in blastocysts (Ma et al., 2010). During T helper cell differentiation, MTA2 acts as a critical player in T cell mediated immunity. Hwang et al. (2010) using affinity purification and mass spectrometry verified that transcription factor GATA3 interacts with MTA2 binding to several regulatory regions in the Th2 cytokine locus and the ifng promoter. In mature T cells, by repressing NK cell-associated transcription, transcription factor BCL11B and the NuRD complex bind to each other to maintain T-cell fate directly (Liao et al., 2023).

In B cell development including in pro-B, pre-B, immature B, marginal zone B cells and abnormal germinal center B cell differentiation during immune responses, MTA2 deficiency in mice leads to increased H3K27 acetylation at both Igll1 and VpreB1 promoters (Lu et al., 2019). MTA2/NuRD complex interacts with AIOLOS/IKAROS in pre-B cells and cooperates with OCA-B in the pre-B cells to immature B cells transition.

In erythroid cells, transcription factor GATA1 could recruit the repressive MeCP1 complex (including MTA2) and the chromatin remodeling ACF/WCRF complex to act as an activator or repressor of different target genes respectively (Rodriguez et al., 2005).

The function of MTA2 in nerve system

Chromodomain helicase DNA binding protein 4 (Chd4), the core catalytic subunit of NuRD complex, along with Mta2, is recruited to genes which are either positively and negatively regulated by Egr2 during peripheral nerve myelination (Hung, Kohnken & Svaren, 2012). The transcription factor A+U-rich element binding factor 1 (AUF1) plays a role in integrating the genetic and epigenetic signals through recruiting HDAC1 and MTA2 to AT-rich DNA elements in developing cortical neurons (Lee et al., 2008).

The expression and clinical significance of MTA2 in cancer

Metastasis is widely recognized as the leading cause of cancer-related mortality and remains the ultimate challenge in oncology (Steeg, 2016). The molecular mechanisms of metastatic tumor cells to infiltrate the surrounding tissue are different, an accurate description and characterization about the movement of tumor cells from primary site to progressively distant organs and colonization that underlie this multistep process is the critical point (Fidler & Kripke, 2015; Nieto, 2013). Among the complicated genes that underlie this multistep process, the metastasis-associated antigen has been shown to work as significant factors to play distinct roles in this dynamic event (Covington & Fuqua, 2014; Malisetty et al., 2017). In particular, MTA1 and MTA2 are frequently upregulated genes in various human cancers and act as pivotal drivers of metastasis. Their functional roles, however, appear to be cancer-type-specific, operating through distinct molecular mechanisms (Kumar & Wang, 2016). Based on the overview of both historic and recent experimental evidence, we dissect the critical roles of MTA2 in tumor progress, the relative schematic diagram is shown in Fig. 3.

Numerous studies on MTA2 function suggest its involvement in cancer progression is likely mediated through its frequently gene amplification and its interactions with a variety of chromatin remodeling factors (Lai & Wade, 2011). MTA2 acts as a central hub with large number of regulatory genes that are involved in different signaling pathways and may work as a molecular marker in various solid tumors (Fu et al., 2011; Kumar, Wang & Bagheri-Yarmand, 2003). The key roles of MTA2 in different cancer types are summarized in Table 1.

Breast cancer

In breast cancer, the function roles and regulatory mechanisms of MTA2 have been extensively investigated. In breast tumor cell line MCF-7, components of NuRD complex, including MTA1/2, are recruited by a 4-hydroxytamoxifen (OHT)-bound estrogen receptor (ER) to the target gene promoters such as pS2 and c-myc (Liu & Bagchi, 2004). Using purification and analysis of the TWIST protein complex by mass spectrometry, TWIST could interact with several components of the Mi2/NuRD complex such as MTA2, RbAp46, Mi2, HDAC2 and recruit them to the E-cadherin promoter for transcriptional repression. Given that TWIST functions as a master regulator of EMT and breast cancer metastasis (Yang et al., 2004), the TWIST/Mi2/NuRD complex has been shown to be essential for breast cancer cell migration and invasion in vitro, as well as for lung metastasis in mice (Fu et al., 2011). Si et al. (2015) provided more evidence to show the difference and relationship between MTA1 and MTA2 in breast cancer cells. We identified GATA3, which is the most highly expressed transcription factor in the luminal epithelial cell population, could form a G9A/NuRD (MTA3) complex to target a cohort of genes including ZEB2. While through the recruitment of G9A/NuRD (MTA1) complex, ZEB2 could in turn, repress the expression of G9A and MTA3. Although the existence of ZEB2/G9A/NuRD (MTA2) complex in vivo was confirmed, MTA2/NuRD complex was not involved in the molecular basis for the opposing action of MTA3 and MTA1 in breast cancer progression (Si et al., 2015).

Breast cancer is a highly heterogeneous malignancy that can be classified into different subtypes based on histological and molecular characteristics. These subtypes include luminal A, luminal B cancers, HER2 positive (HER2+), basal-like and triple-negative breast cancers (Eroles et al., 2012). The role of MTA2 and its potential underlying mechanisms have been investigated in carious contexts. In ERα positive breast cancer, MTA2 has been shown to promote anchorage-independent growth and serve as a potential predictive biomarker. This effect is mediated through the binding of MTA2 to ERα, which subsequently suppresses the transcriptional activity of ERα (Cui et al., 2006). Through interaction with the coactivator AIB1, MTA2 could form a repressive complex, inhibiting CDH1 (encoding E-cadherin) to promote EMT and associate with a pro-metastatic phenotype in ER positive breast cancer metastasis (Vareslija et al., 2021). In ERα-negative breast patients, MTA2 expression is associated with poor prognostic markers and increased risk of early recurrence in retrospective analyses through activation of the Rho signaling pathway through activation of the Rho signaling pathway (Covington et al., 2013). In luminal B breast cancer cells ZR-75-30, the overexpression of MTA1 could down regulate the intrinsic inhibitor of the neutrophil elastase (NE), elafin, to promote the degradation of MTA2, therefore inhibiting the metastasis of ZR-75-30 cells in vitro. They declared the opposite role of MTA1 and MTA2 in the metastasis of ZR-75-30 cells in vitro (Zhang et al., 2019). In triple-negative breast cancer, a cell-based seryl tRNA synthetase (SerRS) promoter driven dual luciferase reporter system is used to screen and verify that 3-(4-methoxyphenyl) quinolin-4(1H)-one (MEQ), is an isoflavone derivative to increase SerRS expression and a potent transcriptional repressor of VEGFA. MEQ regulated SerRS transcription by interacting with MTA2 to suppress the angiogenesis in TNBC allografts and xenografts in mice (Zhang et al., 2020). As breast cancer is a highly heterogeneous cancer, in the future, it is better for the researchers to understand the role of MTA2 and its related mechanisms in the progression of different breast cancer type, the relative schematic diagram is shown in Fig. 4.

Gastric cancer

Gastric cancer ranks as the fifth most commonly diagnosed malignancy worldwide (Bray et al., 2018). Numerous studies have demonstrated that the expression of MTA2 significantly associated with key clinicopathological features of gastric cancer, including tumor invasion, lymph nodes metastasis and tumor node metastasis (TNM) staging (Zhou et al., 2013). Between early-stage gastric cancer tissues of M0 and M1 patients, the mRNA and protein levels of MTA2 are significantly different (Lopes et al., 2019). Transcription factor specificity protein 1 (Sp1) is found to be overexpressed and had positive correlation with MTA2 (Zhou et al., 2012). Furthermore, silencing MTA2 has been shown to markedly inhibit gastric cancer cell invasion both in vitro and in vivo. Mechanistically, Sp1 can bind to the MTA2 promoter region and enhance its transcriptional activity, potentially through upregulating the expression of CD24 and MYLK (Zhou et al., 2013).

Helicobacter pylori (H. pylori) is the main environmental factor and the main causes of gastric cancer (Yang et al., 2020). CircRNAs are universal endogenous noncoding RNAs with highly conserved and stable covalently closed cyclic structure and can act as miRNA sponges to inhibit the activity of miRNAs (Jeck & Sharpless, 2014). In AGS cells, using RNA-seq analysis, circMAN1A2 is proved as one of the upregulated circRNAs after infected with Hp26695. They further revealed that H. pylori could induce circMAN1A2 expression to promote the carcinogenesis of gastric cancer by sponging miR-1236-3p to regulate MTA2 expression in vitro and in vivo (Guo et al., 2022). circMTA2 is another circular RNA which interacted with ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) to restrain MTA2 ubiquitination, and thereby facilitating tumor progression though stabilize MTA2 protein expression (Xie et al., 2024).

In gastric cancer cell lines BGC-823 and MKN28 with MTA2 overexpression, MTA2 has been shown to promote colony formation and tumor growth through the regulation of IL11. However, the mechanism by which the HDAC inhibitor SAHA suppresses IL11 expression remains unclear (Putoczki et al., 2013; Zhou et al., 2015). MicroRNAs are a class of small, evolutionarily conserved non-coding RNAs, approximately 19–25 nucleotides in length, that function as key regulators in cancer development. They can act either as oncogenes or tumor suppressors depending on their target genes and cellular context (Ohtsuka et al., 2015). miR-1236-3p has been identified as a tumor suppressor in gastric cancer by directly targeting MTA2, thereby inhibiting its expression and suppressing the activation of the PI3K/Akt signaling pathway (An et al., 2018). Long non-coding RNAs are a class of RNA transcripts which are longer than 200 nucleotides and involved in gastric cancer development (Ghafouri-Fard & Taheri, 2020; Okugawa et al., 2014), among which, the long non-coding RNA SNHG5 prevents the translocation of MTA2 from the cytoplasm into the nucleus, and thereby interfering with the formation of the NuRD complex to suppresses gastric cancer progression (Zhao et al., 2016), the relative schematic diagram is shown in Fig. 5A.

Pancreatic cancer

Pancreatic cancer (PC) is recognized as a highly lethal malignant, characterized by aggressive biological behavior in recent decades (Hessmann et al., 2017). Despite significant efforts to develop novel therapeutic strategies, the clinical outcomes remain poor, with 5-year survival rates of less than 7% (Pavlidis & Pavlidis, 2018; Waddell et al., 2015). In pancreatic ductal adenocarcinoma, elevated expression of metastasis-associated protein 2 (MTA2) has been observed in tumor tissues. This overexpression is associated with shorter overall survival and has been identified as an independent prognostic factor. Mechanistically, MTA2 promotes PDAC cell proliferation and invasion in vitro, as well as tumor growth in vivo, through its repressive binding to the promoter region of phosphatase and tensin homolog (PTEN) (Si et al., 2019). Snail family transcriptional repressor 1 (Snail), which is a master regulator of epithelial-mesenchymal transition (EMT) and metastasis (Chen et al., 2014; Nishioka et al., 2010), could recruit MTA2 and HDAC1 to suppress PTEN expression and thus activate the PI3K/Akt pathway. These data indicated that in PDAC cancer, MTA2 might work as a subunit of NuRD complex in promotion of PDAC progress. Consistent with the above conclusion, in the study from Chen et al. (2013) they also found the mRNA and protein expression levels of MTA2 are both significantly upregulated in PDAC lesion. The higher MTA2 expression is correlated with poorer tumor differentiation, TNM stage, lymph node metastasis and is considered as a prognostic marker for PDAC. In PDAC cancer cells, MTA2 is transcriptionally upregulated by HIF-1α through an hypoxia response element (HRE) of the MTA2 promoter in response to hypoxia, reciprocally, MTA2 could deacetylate HIF-1α and enhance its stability through interacting with HDAC1 to promote the progression and metastasis of pancreatic carcinoma (Zhu et al., 2018).

Emerging evidence underscores the pivotal roles of miRNAs and lncRNAs in the regulation of PDAC metastasis (Nicoloso et al., 2009). Notably, miR-146a has been found to be downregulated in PDAC cell lines. Treatment of PDAC cells with B-DIM and G2535 has been shown to upregulate expression of miR-146a expression, leading to the suppression of key downstream targets including EGFR, MTA-2, IRAK-1, and NF-κB, thereby inhibiting cell invasion (Li et al., 2010a). Furthermore, re-expression of miR-146a in PC cells results in the attenuation of IRAK1/NF-κB signaling and reduced MTA2 expression (Li et al., 2010b). These findings collectively highlight the tumor-suppressive function of miR-146a in PDAC progression and suggest its potential as a therapeutic target.

lncRNA-MTA2TR (MTA2 transcriptional regulator RNA, AF083120.1) is overexpressed in PC patient tissues and transcriptionally upregulates MTA2 by recruiting activating transcription factor 3 (ATF3) to the MTA2 promoter region. Under hypoxic conditions, MTA2TR is transcriptionally regulated by HIF-1α. A positive feedback loop involving MTA2TR, MTA2 and HIF-1α may play a critical role in regulating of tumorigenesis (Zeng et al., 2019). A schematic representation of MTA2 in PDAC is shown in Fig. 5B.

Hepatocellular carcinoma

In hepatocellular carcinoma, the MTA2 expression level is strongly increased depending on the tumor size and differentiation, and might be a predictor of aggressive phenotypes (Lee et al., 2009), however, the molecular mechanism of MTA2 expression in HCC need further investigation. MTA2 silencing drastically reduces migration and invasion capability through inhibits matrix metalloproteinase 2 (MMP2) and decreases the phosphorylation of the p38MAPK protein (Hsu et al., 2019). As Guan et al. (2019) reported, using ChIP-seq analysis, they identified MTA2 represses a cohort of transcriptional targets including FRMD6, which is a key upstream component of Hippo signaling pathway. Via repressing FRMD6, MTA2 could promote HCC progression through Hippo pathway. Protein tyrosine kinase 7 (PTK7) acted as a downstream factor for MTA2 expression recombinant matrix metalloproteinase 7 (MMP7) reversed the PTK7 knockdown-induced suppression of migration and invasion in HCC cells, which indicate MTA2-FAK-MMP7 axis might be a diagnostic value for HCC patients (Hu et al., 2024). In CD133⁺ HCC cells, MTA2 could interact with HDAC2/CHD4, forms by a part of the NuRD complex and transcriptionally inhibits BDH1, a major rate-limiting enzyme in the metabolic process of ketone bodies, controls the transformation between acetoacetic acid (AcAc) by R-loops, leading to the accumulation of βHB, the increase in H3K9bhb, and a waterfall effect on HCC formation and progression (Zhang et al., 2021).

Colorectal cancer

In colorectal cancer cells, histone acetyltransferase p300 could bind to MTA2 and acetylate MTA2 at K152, while MTA2 acetylation mutation could inhibit the colorectal cancer cells growth and Rat1 fibroblasts invasion capacity. However, the expression level of MTA2 in colorectal cancer tissues and cell lines need further investigation (Zhou et al., 2014). Human β-defensins (hBDs) have chemotactic activity for memory T cells and immature dendritic cells with certain roles in cancer (Sorensen et al., 2005). In colon cancer cells, hBDs could reduce the expression of MTA2 and inhibit the migration ability in a paracrine fashion (Uraki et al., 2014).

Glioma

In glioma tumor tissues, the expression of MTA2 was significantly correlated with tumor grade, while knockdown of MTA2 could significantly inhibit glioma cells growth and invasion in vitro and in vivo (Cheng et al., 2014). MTA2 was considered as a direct target of miR-548b, through repression of MTA2, miR-548b exerts its tumor suppression function in glioma (Pan et al., 2016).

Renal cell carcinoma

During the progression of renal cell carcinoma (RCC), MTA2 expression is markedly upregulated in RCC tissues and correlates with higher tumor grade. Knockdown of MTA2 has been shown to decrease both the activity and protein levels of matrix metalloproteinase-9 (MMP-9), leading to the suppression of RCC cell migration, invasion, and in vivo metastasis. One potential molecular mechanism by which MTA2 contributes to RCC metastasis involves the regulation of miR-133b expression, which directly targets MMP-9. Notably, this regulatory pathway does not appear to influence cancer cell proliferation (Chen et al., 2019).

Cervical cancer

In cervical cancer, elevated expression of MTA2 also indicates poor prognosis of cervical cancer patients (Xiao et al., 2016). Lin et al. (2020) revealed the potential mechanism as that knockdown of MTA2 could elevate the expression of miR-7 and then by direct inhibition of transcription factor specificity protein 1 (Sp1) expression. The enhanced KLK10 expression works as a downstream target gene. Through negatively correlated with Kallikrein-10 (KLK10) expression in vitro and in vivo, they provide a potential therapeutic target in cervical cancer (Lin et al., 2020). As reported by Lin et al. (2021), MTA2 is highly expressed in cervical cancer cells, through regulate matrix metalloproteinase 12 (MMP12) expression, MTA2 is involved in the lung metastasis of cervical cancer.

Ovarian cancer

In ovarian epithelial cancer, MTA2 expression levels in malignant ovarian tissues are significantly elevated compared to those in normal epithelial tissues, and this upregulation is associated with advanced clinical stage, histopathological grade and lymph node metastasis (Ji et al., 2006). Functional analyses of recombinant MTA1 and related MTA2 proteins suggest that the MTA1 protein possesses histone deacetylase activity, highlighting the potential role of MTA family proteins in promoting cancer cell invasion and proliferation (Nicolson et al., 2003).

Nasopharyngeal carcinoma

In nasopharyngeal carcinoma (NPC), MTA2 is identified as a direct target of miR-148b, the tumor suppressive effects of miR-148b is partly through suppression of MTA2 (Wu et al., 2017). However, although MTA2 is associated with malignant behaviors of several types of tumor cells including NPC cell lines, whether MTA2 is indeed involved in the progression of NPC still need further discussion (Wu et al., 2016).

Oral cancer

In human oral cancer, the expression of MTA2 is significantly upregulated in oral cancer tissues and cell lines compared to non-tumor oral tissues and cell lines. Mechanistically, knockdown of MTA2 has been shown to inhibit cell migration and invasion, potentially through the modulation of cytoskeletal dynamics and autophagy, as evidenced by increased expression of phosphorylated cofilin (p-cofilin) and microtubule-associated protein 1 light chain 3-II (LC3-II) (Tseng et al., 2019). In oral squamous cell carcinoma (OSCC), HOX antisense intergenic RNA (HOTAIR) is markedly overexpressed in both tumor tissues and cell lines. HOTAIR functions as a competitive endogenous RNA (ceRNA), effectively sponging miR-326 and thereby relieving the post-transcriptional suppression of MTA2. Elevated MTA2 expression is significantly correlated with advanced clinicopathological features and poor prognosis for patients with OSCC (Tao et al., 2020).

Esophageal carcinoma

In esophageal squamous cell carcinoma (ESCC), MTA2 has been identified as a binding partner of small nucleolar RNA host gene 5 (SNHG5) through RNA pull down assays. Overexpression of SNHG5 results in the downregulation of MTA2 at the transcriptional level and promotes its ubiquitin-mediated proteasomal degradation. Furthermore, the mRNA expression of MTA2 is significantly elevated in ESCC specimens, the negative correlation between SNHG5 and MTA2 might provide a new potential therapeutic strategy for ESCC (Wei et al., 2020). Similarly, Moreover, MTA2 is frequently overexpressed in ESCC tissue and is closely associated with aggressive tumor phenotypes and poor prognosis. Mechanistically, MTA2 promotes tumor growth, metastasis, and epithelial-mesenchymal transition (EMT) via a novel positive feedback loop involving eukaryotic translation initiation factor 4E (EIF4E) and Twist (Dai et al., 2020).

Non-small cell lung cancer

In non-small cell lung cancer (NSCLC), MTA2 is predominantly localized in both nucleus and cytoplasm in cancer cells. Notably, a higher Ki-67 proliferation index has been significantly associated with nuclear MTA2 positive tumors. However, there is no significant difference in cytoplasmic MTA2 status with Ki-67 proliferation index (Liu et al., 2012). MTA2 has been identified as a non NF-κB target gene regulated by IKK2, MTA2 negatively regulates NF-κB signaling to reduce lung tumor growth and inflammation. MTA2 exerts opposite functions as it initially inhibited primary lung cancer growth but later favored metastasis by sustained inflammatory response at the later phases (El-Nikhely et al., 2020). In NSCLC, the expression of MTA2 has negative correlation with differentiation degree, but positive correlation with clinical stage and lymph node metastasis (Wang et al., 2010). Furthermore, upregulation of δ-Catenin, an adherens junction-associated protein, may regulate MTA2 through Kaiso—a transcription factor—in a DNA methylation-dependent manner, leading to adverse clinical outcomes in non-small cell lung cancer (NSCLC) (Dai et al., 2011).

Thyroid cancer

In papillary thyroid cancer (PTC), circular RNA circ-NCOR2 has been found to be upregulated both PTC tissues and cell lines. It promotes PTC cell progression by enhancing MTA2 expression through sponging miR-615-5p (Luan et al., 2020).

Thymomas

In thymomas, nuclear MTA2 is detected in 70.8% of the thymomas, there are good consistencies and correlations between cytoplasmic p120 catenin, cytoplasmic Kaiso and nuclear MTA2 expression. These three protein correlated directly with histological type and Masaoka stage of thymomas, and might be used as potential biomarkers to predict the biological behavior (Wang et al., 2012). However, the mechanism underlying the relationship between MTA2 and Kaiso remains unknown.