MTA1 Expression Research Articles

Subcellular expression of MTA1, HIF1A and p53 in primary tumor predicts aggressive triple negative breast cancers: a meta-analysis based study.

The prevalence of TNBC in India is higher compared to western countries. There is a multitude of biomarkers associated with different clinical outcomes of TNBC with contradictory reports. Identification of a set of specific biomarkers from the very many number of proteins reported in the literature to predict prognosis of TNBC is an urgent clinical need. A systematic review of key molecular biomarkers in cohort studies that have been investigated for their role in breast cancer prognosis was conducted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology was followed. A meta-analysis was used to evaluate their pooled hazard ratio (HR) and the corresponding 95% confidence interval (95% CI) statistically. Immunohistochemical characterization of the meta-analyzed markers were performed in a cohort of 200 retrospective TNBC and 100 non TNBC patient tissues. Kaplan-Meier plot were used to evaluate disease free survival (DFS), and overall survival (OS). Cox regression models were used to evaluate predictors of DFS and OS. Using a meta-analytical approach, we consolidated the biomarker signatures associated with survival outcomes in breast cancers. The promising markers that emerged for the prediction of DFS and OS included E-Cadherin, Survivin, p53, MTA1, HIF1A, CD133, Vimentin and CK5/6. Evaluation of these markers in tumor tissue revealed that subcellular localization of p53, MTA1 and HIF1A had a significant association in predicting TNBC prognosis. Kaplan Meier plot revealed that p53 (OS p = 0.007, DFS p = 0.004), HIF 1A (OS p = 0.054, DFS p = 0.009) and MTA1 (OS p = 0.043, DFS = p = 0.001) expression in the primary tumor tissue were found to be significantly correlated with poor OS and DFS, whereas expression of Survivin (DFS p = 0.024) and E Cadherin (DFS p = 0.027) correlated with DFS alone in TNBC. Univariate analysis revealed that p53, HIF1A and MTA1 could be independent prognostic markers. Our study suggests cytoplasmic over expression of HIF1A, nuclear over expression of MTA1 and mutated p53 in the primary tumor tissue of TNBC have significance as markers predicting survival of TNBC patients.

GDNF facilitates the differentiation of ADSCs to Schwann cells and enhances nerve regeneration through GDNF/MTA1/Hes1 axis

Adipose tissue-derived stem cells (ADSCs) are a kind of stem cells with multi-directional differentiation potential, which mainly restore tissue repair function and promote cell regeneration. It can be directionally differentiated into Schwann-like cells to promote the repair of peripheral nerve injury. Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the repair of nerve injury, but the underlying mechanism remains unclear, which seriously limits its further application.The study aimed to identify the molecular mechanism by which overexpression of glial cell line–derived neurotrophic factor (GDNF) facilitates the differentiation of ADSCs into Schwann cells, enhancing nerve regeneration after injury. In vitro, ADSCs overexpressing GDNF for 48 h exhibited changes in their morphology, with 80% of the cells having two or more prominences. Compared with that of ADSCs, GDNF-ADSCs exhibited increased expression of the Schwann cell marker S100, nerve damage repair-related factors.ADSC cells in normal culture and ADSC cells were overexpressing GDNF(GDNF-ADSCs) were analysed using TMT-Based Proteomic Analysis and revealed a significantly higher expression of MTA1 in GDNF-ADSCs than in control ADSCs. Hes1 expression was significantly higher in GDNF-ADSCs than in ADSCs and decreased by MTA1 silencing, along with a simultaneous decrease in the expression of S100 and nerve damage repair factors. These findings indicate that GDNF promotes the differentiation of ADSCs into Schwann cells and induces factors that accelerate peripheral nerve damage repair.

Biological function and regulatory mechanism of mta2 expression in bladder cancerous cells

Purpose: To study the function, regulation, and potential clinical use of mta2 gene in carcinoma of the bladder.
 Methods: Viral vector and si-mta2 were transfected into both T24 and EJ bladder cancer cells, for induction of overexpression and knockdown of metastasis-associated gene 2 (mta2), respectively. In vitro invasiveness and migratory potential of cell lines were assayed using Matrigel and Transwell procedures, respectively, under the two mta2 expression conditions.
 Results: Transwell migration data revealed that overexpressed mta2 protein significantly enhanced the migratory capacity of T24 bladder cancer cell line, while knockdown of mta2 significantly reduced the migration of EJ bladder cancer cell line (p < 0.01). Matrigel invasion assay showed that overexpression of mta2 protein significantly enhanced the invasive potential of T24 bladder cancer cell line, but knockdown of mta2 significantly (p < 0.01) reduced the invasive capacity of EJ bladder cancer cell line. There was a lower amount of E-cadherin protein in T24 bladder cancer cell line overexpressing mta2 than in cd511b-transfected and un-transfected cells, but N-cadherin protein level was significantly higher. Furthermore, there was a significantly higher amount of E-cadherin protein expression in EJ bladder cancer cell line with mta2 knockdown than in si-NC transfection and un-transfected cells (p < 0.01).
 Conclusion: Knockdown of mta2 inhibits the proliferation, migration and invasion of bladder cancer cell lines through a mechanism related to the inhibition of epithelial-mesenchymal transition-related process proteins.

Expression and Significance of MTA2 and CPNE1 in Cervical Squamous Cell Carcinoma.

The aim of this study was to investigate the expression and clinical significance of MTA2 and CPNE1 proteins in cervical squamous cell carcinoma. In this study, high-risk human papillomavirus (HPV) typing was performed on cervical cancer tissues. Reverse transcription polymerase chain reaction and immunochemical EliVision method were used to examine the expressions of MTA2 and CPNE1 in the cervix, and their relationship with clinicopathologic features. We found that it is mainly distributed in these types, namely HPV-16 (23.8%), HPV-18 (20.9%), HPV-53 (17.1%), HPV-52 (15.5%), HPV-82 (11.7%), HPV-56 (10.8%). The expressions of MTA2 and CPNE1 in cervical squamous cell carcinoma tissues were significantly higher than those in normal tissues ( P <0.01). The expressions of MTA2 and CPNE1 were correlated with FIGO stage, degree of differentiation, and lymph node metastasis of cervical cancer ( P <0.05), but not with the patient's age ( P >0.05). The rank correlation coefficient of MTA2 and CPNE1 protein expression in cervical squamous cell carcinoma was 0.668 ( P <0.01), and the 2 expressions were positively correlated. MTA2 and CPNE1 are closely related to the occurrence and development of cervical squamous cell carcinoma and may play a synergistic role in the evolution of cervical squamous cell carcinoma.

Function of TRPC1 in modulating hepatocellular carcinoma progression.

The liver is the main organ of metabolism in the human body, and it is easy to suffer from hepatitis, cirrhosis, liver cancer, and other diseases, the most serious of which is liver cancer. Worldwide, liver cancer is the most common and deadly malignant tumor, the third leading cause of cancer death in the world. Based on TCGA and ICGC databases, our research discovered the important role of TRPC1 in liver cancer through bioinformatics. The results showed that TRPC1 was over-expressed in hepatocellular carcinoma, and the higher the expression level of TRPC1, the worse the OS and the lower the survival rate. TRPC1 was a risk factor affecting the overall survival probability of hepatocellular carcinoma patients. By analyzing the function of the TRP family in liver cancer, TRPC1 might promote the occurrence of liver cancer by up-regulating common signal pathways in tumors such as tumor proliferation signature, and down-regulating important metabolic reactions such as retinol metabolism. In addition, TRPC1 could promote the development of liver cancer by up-regulating the expression of ABI2, MAPRE1, YEATS2, MTA3, TMEM237, MTMR2, CCDC6, AC069544.2, and NCBP2 genes. These results illustrate that TRPC1 is very valuable in the study of liver cancer.

Retraction: MiR-30e-5p inhibits the migration and invasion of nasopharyngeal carcinoma via regulating the expression of MTA1.

This Retraction follows an Expression of Concern relating to this article previously published by Portland Press. This article is being retracted from Bioscience Reports at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to concerns regarding the Kaplan-Meier graphs of Figure 1F and G, as well as the western blots. The graphs appear to show an implausible date range, and the western blots have concerning features such as the shapes of the bands and absence of any detectable background. The authors have been contacted with regards to the retraction and have not responded to the Journal's queries or the concerns raised. Given the extent of the issues raised, the Editorial Board stand by the decision to retract the article.

MTA1 as negative prognostic marker in vulvar carcinoma

PurposeVulvar cancer is the fourth most common malignancy of the female genital tract after endometrial, ovarian, and cervical carcinoma and affects mainly elderly women. In 2020 there were registered more than 17,000 deaths worldwide related to vulvar carcinoma. Data about target-based therapies and predictive biomarkers for vulva carcinomas are rare so far. The metastasis-associated gene MTA1 is a transcriptional repressor with a potential effect on cancer. Expression of MTA1 was found to be significantly enhanced in gynecological malignancies as breast or ovarian cancer tissues with advanced cancer stages and higher FIGO grading, indicating an important role of MTA1 in the progression of those tumor entities. Due to the lack of information around MTA1 and its significance regarding vulvar carcinoma, this study focuses on the expression of MTA1 in vulvar carcinoma and its correlation to clinicopathological characteristics and prognosis.MethodsA total of 157 paraffin-embedded vulvar cancer tissues were immunohistochemically stained and examined for MTA1 expression by using the immunoreactive score. Subsequently, the values were correlated with clinicopathological parameters.ResultsMTA1 was found to be expressed in 94% of the patients in the cytoplasm and 91% in the nucleus. Cytoplasmatic expression of MTA1 was significantly increased in non-keratinizing squamous cell carcinoma and in vulvar carcinoma of the condylomatous type, compared to keratinizing squamous cell carcinoma and vulvar carcinoma of the verrucous type. High MTA1 expression in the nucleus was associated with advanced tumor size as well as higher FIGO grading. In addition, p16 negative vulvar carcinomas showed a higher nuclear expression of MTA1 compared to p16 positive vulvar carcinomas. Suprisingly, Kaplan–Meier analysis showed a significantly lower disease-free survival in tumor samples without a nuclear expression of MTA1.ConclusionsMTA1 was identified as a negative prognostic marker for vulvar carcinoma associated with advanced tumor stage and FIGO grading. A possible explanation could be that the antibody used for this study does not bind to a possible mutation in the C terminal region of MTA leading to negative immunohistochemical staining and this can be correlated with early recurrence in patients with vulvar carcinoma.

Circ_0124055 promotes the progression of thyroid cancer cells through the miR-486-3p/MTA1 axis.

Thyroid cancer is one of the malignancy cancers. CircRNA, a non-coding RNA, plays an important role in the development of cancer. The relationship and roles of circ_0124055, miR-486-3p and MTA1 in thyroid cancer have not been reported. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to analyze the RNA levels of circ_0124055, miR-486-3p and MTA1. Western blot was conducted to analyze the protein levels of MTA1, Epithelial cadherin (E-cadherin) and Neuro cadherin (N-cadherin). Subcellular localization assay was used to analyze circ_0124055 location in thyroid cancer cells. Colony formation assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay were carried out to analyze cell proliferation. Cell migration and invasion were analyzed by wound-healing assay and transwell assay. Flow cytometry assay was performed to investigate cell apoptosis. Dual-luciferase reporter assay and RIP assay were employed to analyze the interactions among circ_0124055, miR-486-3p and MTA1. Immunohistochemical (IHC) assay was performed to assess the expression of Ki67, MTA1 and E-cadherin in tumor tissues. Thyroid cancer tumor growth in vivo was evaluated by tumor xenograft mouse model assay. The expression of circ_0124055 was up-regulated in tumor tissues and cells. Knockdown of circ_0124055 could inhibit thyroid cancer cell proliferation, migration and invasion and promote cell apoptosis, accompanied by the dysregulation of E-cadherin and N-cadherin expression. Circ_0124055 could target miR-486-3p, and miR-486-3p could target MTA1. MiR-486-3p inhibitor could restore the effect of circ_0124055 knockdown in the progression of thyroid cancer. Moreover, MTA1 overexpression weakened the inhibitory effects of miR-486-3p mimics on the progression of thyroid cancer. Further, circ_0124055 could influence tumor growth in vivo. Circ_0124055 promoted the progression of thyroid cancer cells through the miR-486-3p /MTA1 axis.

Analysis of ADORA2A, MTA1, PTGDS, PTGS2, NSF, and HNMT Gene Expression Levels in Peripheral Blood of Patients with Early Stages of Parkinson's Disease.

Parkinson's disease (PD) is a common chronic, age-related neurodegenerative disease. This disease is characterized by a long prodromal period. In this context, it is important to search for the genes and mechanisms that are involved in the development of the pathological process in the earliest stages of the disease. Published data suggest that blood cells, particularly lymphocytes, may be a model for studying the processes that occur in the brain in PD. Thus, in the present work, we performed an analysis of changes in the expression of the genes ADORA2A, MTA1, PTGDS, PTGS2, NSF, and HNMT in the peripheral blood of patients with early stages of PD (stages 1 and 2 of the Hoehn-Yahr scale). We found significant and PD-specific expression changes of four genes, i.e., MTA1, PTGS2, NSF, and HNMT, in the peripheral blood of patients with early stages of PD. These genes may be associated with PD pathogenesis in the early clinical stages and can be considered as potential candidate genes for this disease. Altered expression of the ADORA2A gene in treated PD patients may indicate that this gene is involved in processes affected by antiparkinsonian therapy.

Zinc-finger protein CXXC5 promotes breast carcinogenesis by regulating the TSC1/mTOR signaling pathway

CXXC5, a member of the CXXC family of zinc-finger proteins, is associated with numerous pathological processes. However, the pathophysiological function of CXXC5 has not been clearly established. Herein, we found that CXXC5 interacts with the CRL4B and NuRD complexes. Screening of transcriptional targets downstream of the CXXC5-CRL4B-NuRD complex by next-generation sequencing (chromatin immunoprecipitation sequencing) revealed that the complex regulates the transcriptional repression process of a cohort of genes, including TSC1 (tuberous sclerosis complex subunit 1), which play important roles in cell growth and mammalian target of rapamycin signaling pathway regulation, and whose abnormal regulation results in the activation of programmed cell death-ligand protein 1 (PD-L1). Intriguingly, CXXC5 expression increased after stimulation with vitamin B2 but decreased after vitamin D treatment. We also found that the CXXC5-CRL4B-NuRD complex promotes the proliferation of tumor cells invitro and accelerates the growth of breast cancer invivo. The expression of CXXC5, CUL4B, and MTA1 increased during the occurrence and development of breast cancer, and correspondingly, TSC1 expression decreased. Meanwhile, a high expression of CXXC5 was positively correlated with the histological grade of high malignancy and poor survival of patients. In conclusion, our study revealed that CXXC5-mediated TSC1 suppression activates the mammalian target of rapamycin pathway, reduces autophagic cell death, induces PD-L1-mediated immune suppression, and results in tumor development, shedding light on the mechanism of the pathophysiological function of CXXC5.

Vascular Disruptive Hydrogel Platform for Enhanced Chemotherapy and Anti-Angiogenesis through Alleviation of Immune Surveillance.

Patients undergoing immunotherapy always exhibit a low-response rate due to tumor heterogeneity and immune surveillance in the tumor. Angiogenesis plays an important role in affecting the status of tumor-infiltrated lymphocytes by inducing hypoxia and acidosis microenvironment, suggesting its synergistic potential in immunotherapy. However, the antitumor efficacy of singular anti-angiogenesis therapy often suffers from failure in the clinic due to the compensatory pro-angiogenesis signaling pathway. In this work, classic injectable thermosensitive PLGA-PEG-PLGA copolymer was used to construct a platform to co-deliver CA4P (vascular disruptive agent) and EPI for inducing immunogenic cell death of cancer cells by targeting the tumor immune microenvironment. Investigation of 4T1 tumor-bearing mouse models suggests that local administration of injectable V+E@Gel could significantly inhibit the proliferation of cancer cells and prolong the survival rate of 4T1 tumor-bearing mouse models. Histological analysis further indicates that V+E@Gel could effectively inhibit tumor angiogenesis and metastasis by down-regulating the expression of CD34, CD31, MTA1 and TGF-β. Moreover, due to the sustained release kinetics of V+E@Gel, its local administration relieves the immune surveillance in tumor tissues and thus induces a robust and long-lasting specific antitumor immune response. Overall, this work provides a new treatment strategy through the mediation of the tumor immune microenvironment by vascular disruption to fulfill enhanced chemotherapy and immunotherapy.

Genome-wide CRISPR screen identifies MTA3 as an inducer of gemcitabine resistance in pancreatic ductal adenocarcinoma

Gemcitabine (GEM) resistance is one of the major causes of treatment failure in pancreatic ductal adenocarcinoma (PDAC) in clinic. Here, through CRISPR/Cas9 activation library screen, we found that MTA3 mediates the GEM resistance of PDAC and thus might be a potential therapeutic target for combination chemotherapy. The CRISPR library screening showed that MTA3 is the most enriched gene in the surviving GEM-treated cells, and bioinformatic and histology analysis implied its high correlation with GEM resistance. MTA3 promoted GEM resistance of PDAC cells in in vitro and in vivo experiments. Mechanistically, as a component of the Mi-2/nucleosome remodeling and deacetylase transcriptional repression complex, MTA3 transcriptionally represses CRIP2, a transcriptional repressor of NF-κB/p65, activating NF-κB signaling and consequently leading to GEM resistance. Furthermore, the treatment of GEM increases MTA3 expression in PDAC cells via activating STAT3 signaling, thereby inducing the acquired chemoresistance of PDAC to GEM. In patients derived xenografts (PDX) mouse model, Colchicine suppresses the expression of MTA3 and increases the sensitivity of tumor cells to GEM. Based on these findings, MTA3 plays a key role in GEM resistance in pancreatic cancer and is a promising therapeutic target for reversing GEM chemotherapy resistance.

Epithelial-mesenchymal transition and cancer stem cells: A route to acquired cisplatin resistance through epigenetics in HNSCC.

Chemoresistance is associated with tumor recurrence, metastases, and short survival. Cisplatin is one of the most used chemotherapies in cancer treatment, including head and neck squamous cell carcinoma (HNSCC), and many patients develop resistance. Here, we established cell lines resistant to cisplatin to better understand epigenetics and biological differences driving the progression of HNSCC after treatment. Cisplatin resistance was established in CAL-27 and SCC-9 cell lines. Gene expression of HDAC1, HDAC2, SIRT1, MTA1, KAT2B, KAT6A, KAT6B, and BRD4 indicated the cisplatin activates the epigenetic machinery. Increases in tumor aggressiveness were detected by BMI-1 and KI-67 in more resistant cell lines. Changes in cellular shape and epithelial-mesenchymal transition (EMT) activation were also observed. HDAC1 and ZEB1 presented an opposite distribution with down-regulation of HDAC1 and up-regulation of ZEB1 in the course of chemoresistance. Up-regulation of ZEB1 and BMI-1 in patients with HNSCC is also associated with a poor response to therapy. Cancer stem cells (CSC) population increased significantly with chemoresistance. Down-regulation of HDAC1, HDAC2, and SIRT1 and accumulation of Vimentin and ZEB1 were observed in the CSC population. Our results suggest that in the route to cisplatin chemoresistance, epigenetic modifications can be associated with EMT activation and CSC accumulation which originate more aggressive tumors.

Bone Marrow Stromal Cells Promotes Morphological Senescence of Prostate Cancer Cells and Inhibits Metastasis Associated 1 Gene Level

This study assessed the mechanism of Bone Marrow Stromal Cells (BMSCs) in prostate cancer (PC) and its effect on MTA-1 gene and PC cell senescence. PC-3 cells were assigned into QL group (prostate cancer group: normal culture) and GS group (BMSCs group: treated with BMSCs) followed by analysis of MTA-1 level, cell senescence, apoptosis and invasion. MTA-1 level in QL group (0.83±0.07) was significantly higher than GS group (0.14±0.02) (P &lt; 0.05), indicating that BMSCs had an inhibitory effect on MTA-1 expression. Similar change of MTA-l mRNA was also found with higher level in QL group than GS group (P &lt; 0.05). Cell senescence was found in QS group but not QL group, indicating that BMSCs promote cell senescence. Compared with GS group, QL group has a higher cell number in G0/G1 (67.13±6.45%) and S (19.59±3.35%) than GS group (G0/G1:50.51±2.19% and S: 11.42±1.61%) but lower G2/M (QL: 15.97±3.59% versus GS: 32.25±3.24%). QL group had significantly lower cell apoptosis rate at 35 h (5.21±1.2%) and 45 h (3.97±0.95%) than GS group at 35 h (17.85±1.23%), 45 h (10.21±1.26%) with elevated number of invasions. In conclusion, BMSCs promote PC-3 cell senescence and apoptosis by inhibiting the expression of MTA-1 and reduce cell invasion ability.

CircMAN1A2 is upregulated by Helicobacter pylori and promotes development of gastric cancer

Helicobacter pylori (H. pylori) is one of the main causes of gastric cancer. It has been reported that circRNAs play a vital role in the development of multiple types of cancer. However, the role of H. pylori-induced circRNAs in the development of gastric cancer has not been studied. In this study, we found that H. pylori could induce the upregulation of circMAN1A2 in AGS and BGC823 cells independent of CagA. The downregulation of circMAN1A2 could inhibit the proliferation, migration and invasion of gastric cancer cells, and circMAN1A2 could promote the progression of gastric cancer induced by H. pylori by sponging miR-1236-3p to regulate MTA2 expression. Furthermore, circMAN1A2 knockdown inhibited xenograft tumour growth in vivo, and the overexpression of circMAN1A2 was associated with the progression of gastric cancer. Hence, Helicobacter pylori induced circMAN1A2 expression to promote the carcinogenesis of gastric cancer, and circMAN1A2 might be a new potential diagnostic marker and therapeutic target for gastric cancer.

The effect of progesterone administration on the expression of metastasis tumor antigens (MTA1 and MTA3) in placentas of normal and dexamethasone-treated rats.

Dexamethasone (DEX) induces intrauterine growth restriction (IUGR)in pregnant rats. IUGR can occur due to apoptosis of trophoblasts, which is believed to be inhibited by progesterone (P4). A group of genes called MTAs play a role in proliferation and apoptosis. MTA1 upregulates trophoblasts proliferation and differentiation, while MTA3 downregulates proliferation and induces apoptosis. Hence, we hypothesized that during IUGR, placental MTA1 decreases and MTA3 increases and this is reversed by P4 treatment. Pregnant Sprague-Dawley rats were divided into 4 groups based on daily intraperitoneal injections: control (C, saline), DEX (DEX, 0.2mg/kg/day), DEX and P4 (DEX + P4, DEX: 0.2mg/kg/day, P4: 5mg/kg/day) and P4-treated (P4, 5mg/kg/day) groups. Injections were started on 15 dg until the day of dissection (19 or 21 dg). Gene and protein expressions of MTA1 and MTA3 were studied in the labyrinth (LZ) and basal (BZ) zones using real-time PCR and Western blotting, respectively. DEX treatment induced 18% reduction in fetal body weight (p < 0.001) and 30% reduction in placental weight (p < 0.01). Maternal P4 level was also significantly lower in DEX treated groups (p < 0.05). MTA1 expression was decreased in the LZ (gene, p < 0.001) and BZ (protein p < 0.01), while MTA3 protein expression was upregulated in the LZ with DEX treatment (p < 0.001). These changes were reversed with P4 treatment. The findings of the present study indicate that DEX induces IUGR through changing the expression of placental MTA1 and MTA3 antigens and P4 improved pregnancy outcome by preventing the changes in MTAs expression.

Role of lncRNA AGAP2-AS1 in Breast Cancer Cell Resistance to Apoptosis by the Regulation of MTA1 Promoter Activity.

Introduction Breast cancer (BC) is a common malignant tumor affecting women across the world. LncRNAs are frequently implicated in the course of BC. The current study set out to determine the specific effect of lncRNA AGAP2-AS1 on BC cell resistance to apoptosis. Methods AGAP2-AS1 expression patterns in BC tissues and cells were evaluated. si-AGAP2-AS1 was transfected into MCF-7 cells, followed by the assessment of cell proliferation and apoptosis. In addition to detection of MTA1 expression patterns, the binding relation between AGAP2-AS1 and HuR was verified using RNA pull-down and RNA immunoprecipitation. Next, the regulation enrichment of AGAP2-AS1- and HuR to H3K27ac recruitment in the MTA1 promoter was analyzed. MCF-7 cell resistance to apoptosis was observed after the combined experiment of histone deacetylase inhibitor M344 and si-AGAP2-AS1. Lastly, xenografts tumors were established to detect tumor weight and volume, tumor apoptosis and growth as well as expression of AGAP2-AS1 and MTA1. Results AGAP2-AS1 was overexpressed in BC tissues and cells, and AGAP2-AS1 silencing inhibited cell proliferation but facilitated apoptosis. Physiologically, AGAP2-AS1 bound to HuR to stabilize its own expression, and AGAP2-AS1-HuR complex upregulated H3K27ac levels in the MTA1 promoter region to elevate MTA1 promoter activity and MTA1 expression. H3K27ac upregulation partially-annulled the promotive effect of si-AGAP2-AS1 on BC apoptosis by upregulating MTA1. si-AGAP2-AS1 in vivo inhibited MTA1 expression to enhance apoptosis and suppress tumor growth. Conclusion Collectively, our findings indicated that AGAP2-AS1 bound to HuR to stabilize its own expression, and AGAP2-AS1-HuR complex enhanced H3K27ac levels in the MTA1 promoter region to improve MTA1 promoter activity and MTA1 expression in BC cells, so as to augment BC cell resistance to apoptosis.

FOXP3 Inhibits the Metastasis of Breast Cancer by Downregulating the Expression of MTA1

BackgroundFOXP3, as a tumour suppressor gene, has a vital function in inhibiting the metastasis of breast cancer cells, but the mechanisms by which it inhibits metastasis have not been fully elucidated. This study intended to explore a new mechanism by which FOXP3 inhibits breast cancer metastasis.MethodsBioinformatic analysis was performed to identify potential downstream molecules of FOXP3. The function of FOXP3 in inhibiting MTA1 expression at the mRNA and protein levels was verified by real-time PCR and Western blot analysis. The interaction between FOXP3 and the MTA1 promoter was verified by transcriptomic experiments. In vitro and in vivo experiments were used to determine whether the regulation of MTA1 by FOXP3 affected the invasion and migration of breast cancer cells. Immunohistochemistry was adopted to explore the correlation between the expression levels of FOXP3 and MTA1 in breast cancer samples.ResultsBioinformatics-based sequencing suggested that MTA1 is a potential downstream molecule of FOXP3. FOXP3 downregulated the expression of MTA1 in breast cancer cells by directly inhibiting MTA1 promoter activity. Importantly, FOXP3’s regulation of MTA1 affected the ability of breast cancer cells to invade and metastasize in vitro and in vivo. Moreover, analysis of clinical specimens showed a significant negative correlation between the expression levels of FOXP3 and MTA1 in breast cancer.ConclusionWe systematically explored a new mechanism by which FOXP3 inhibits breast cancer metastasis via the FOXP3-MTA1 pathway.

Epigenetic Plasticity in ATP-Dependent Chromatin Remodeling Complexes in Human Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is the second most common leukemia worldwide with a median age of ~65 years at diagnosis. Myelodysplastic syndromes (MDS) are hematopoietic stem/progenitor cell (HSPC)-initiated clonal disorders of aged individuals that may transform into secondary AML. Cancer genome sequencing studies have identified somatic mutations in genes that encode chromatin regulators. However, mutational profiling alone may not help identify tumor associated transcriptional plasticity, one important hallmark in tumorigenesis. Nucleosome remodeler and deacetylase (NuRD) is an ATP-dependent chromatin remodeling complex, regulating cell-fate commitment and transcriptional architecture. Loss of Mi-2β (CHD4, ATPase subunit of NuRD) causes erythroid leukemia in mice. However, recent report suggests that CHD4 depletion inhibits AML development (Sperlazza J, et al., Blood 2015). Therefore, NuRD involvement in MDS/AML remains incompletely understood.We have analyzed gene expression of NuRD subunits in a cohort of elderly (median age 60 yrs) patients presenting with MDS. Expression of MBD3 , an integral scaffold of NuRD, but not other NuRD subunits, was significantly downregulated (2.5-fold; P = 0.004) in MDS (n=24) bone marrow (BM) CD34+ HSPCs compared to age-matched normal (n=6) BM CD34+ cells. Clonal hematopoiesis emerges as an integral component of hematopoietic aging and myeloid malignancies. We asked whether loss of MBD3 expression was associated with HSPC-aging. MBD3 expression was similar (P = 0.194) in CD34+ HSPCs derived from umbilical cord blood (n=6) and aged normal BM. Next, we extended our RT-qPCR analysis in a cohort of de novo AML (n=82) patients, which also suggested significant loss (3.5-fold; P = 0.003) of MBD3 in AML BM nuclear cells (BMNCs) compared to normal BM HSPCs. In addition, there were loss of expression of MTA1, MTA2, MTA3 , RBBP7 subunits (P < 0.001) in AML. Immunoblot analysis suggested dramatic loss of MBD3 in AML BMNCs, and co immunoprecipitation (Co-IP) analysis using antibody against intact CHD4, demonstrated association of residual NuRD subunits in primary AML cells. Sucrose density gradient centrifugation analysis further confirmed nucleation of residual NuRD (hereafter known as NuRDΔ) in AML BMNCs. Essentially these data identify HSPC-autonomous loss of MBD3, and indicate NuRDΔ nucleation as a general phenomenon in AML.We sought to determine chromatin occupancy of NuRDΔ in primary AML cells using ChIP-sequencing. CHD4 ChIP-seq identified ~ 9,000 target genes on average in AML (n=3) BMNCs. Interestingly, RNA-seq analysis in matched AML cohort compared to normal hematopoietic cells, and functional annotation clustering using Gene Ontology (GO)-terms on the CHD4 ChIP-seq identified gene set suggested an enrichment of transcripts that are involved in regulating small GTPase signaling, cytoskeletal organization and cell trafficking. Small GTPases play pivotal role in regulating myeloid leukemia cell engraftment and survival (Sengupta A, et al., Blood 2010; Thomas EK, Cancelas JA et al., Cancer Cell 2007). Lentivirus-mediated loss of function experiments and biochemical studies suggested NuRDΔ contribution in myeloid leukemia cell-microenvironment interaction. We further tested the hypothesis whether NuRDΔ function involves MBD2/MeCP1-mediated transcriptional dysregulation. Importantly, MBD3 antagonistically regulated H3K27me3, and consistent with this observation a subset of CHD4 ChIP-seq occupied genes in AML significantly overlapped with H3K27me3 binding. Pathway analysis suggested that those genes are involved in RNA transport and metabolism. Pharmacological inhibition of H3K27me3-methyl transferase activity along with small GTPase inhibition attenuated AML cell survival. SWI/SNF, another ATP-dependent chromatin remodeler, represents one of the most commonly mutated (~ 20%) chromatin modulators in human cancer. Co-IP experiments demonstrated interaction between NuRDΔ and leukemic SWI/SNF (having altered stoichiometry) in AML, and ChIP-seq analysis further identified leukemic SWI/SNF and NuRDΔ co-occupancy in AML BMNCs. In summary, we illustrate that in human primary AML cells, there is absence of specific subunits of NuRD complex; NuRDΔ, crosstalks with leukemic SWI/SNF and effects leukemia cell survival and transcriptional dysregulation. DisclosuresNo relevant conflicts of interest to declare.

Expression of Concern: MiR-30e-5p inhibits the migration and invasion of nasopharyngeal carcinoma via regulating the expression of MTA1.

The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates.