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BackgroundOverexpression of Metastasis-associated protein 1 (MTA1) in various cancer cells promotes tumor invasion and migration and predicts cancer patients’ poor prognosis. The pilot RNA-Seq data from our laboratory indicated that Epithelial cell adhesion molecule (EpCAM) was statistically reduced in MTA1-silencing cells. EpCAM has been recognized as more than a mere cell adhesion molecule and recent findings have revealed its causal role in mediating migratory and invasive capacity. Thus, this study was aimed to explore whether MTA1 was able to upregulate EpCAM expression and, consequently, modulate its effects on invasion and migration of the lung cancer cells as well as patients’ prognosis.MethodsWe checked the EpCAM expression by overexpressing or silencing MTA1 in lung cancer cells. Furthermore, these lung cancer cells with stably overexpressed or silenced MTA1 were transfected with siEpCAM or EpCAM-expressing plasmids and then subjected to western blot, invasion and migration assays. In addition, patients (n = 118) with early-stage lung cancer were enrolled in this study to confirm the correlations between MTA1 and EpCAM and pathoclinical parameters by using immunohistochemistry (IHC). All statistical analyses were performed with SPSS 20.0 statistical software.ResultsMTA1 upregulated EpCAM expression in lung cancer cell lines, and EpCAM overexpression rescued the inhibitory effects by silencing MTA1 on cell invasion and migration in vitro. What’s more, both MTA1 and EpCAM, correlated to each other, were overexpressed in lung cancer tissues and significantly correlated with their clinical stages, tumor diameters, lymph node metastasis. Multivariate analysis indicated that local advancement (p = 0.03), MTA1 overexpression (p = 0.001) and EpCAM overexpression (p = 0.045) of the lung cancer tissues remained significant in predicting unfavorable overall survival.ConclusionsWe revealed a new molecular mechanism of MTA1-mediated invasion and metastasis in lung cancer through downstream target EpCAM, and interfering with EpCAM function may be a novel therapeutic strategy for treatment of MTA1-overexpressing lung carcinoma.

Abstract. As a component of the nuclear remodeling and deacetylation complex (NuRD complex), metastasis-associated gene 1 (MTA1) has been reported to play a key role in cancer malignancy. However, whether MTA1 functions in small cell lung cancer (SCLC) malignant behavior and whether it is feasible to be used as a therapeutic target have not been evaluated. The present study aimed to investigate the effects of MTA1 downregulation on SCLC malignancy. First we demonstrated the overexpression of MTA1 in SCLC specimens. After knocking down the MTA1 level by specific siRNA sequence, the biological consequences on proliferation, migration, invasion and apoptosis were evaluated. The results showed that MTA1 silencing had potent suppressive effects on SCLC proliferation, migration and invasion. Apoptosis but not cell cycle arrest was induced in the MTA1-silenced SCLC cells. In summary, MTA1 plays a critical role in regulating the malignant behaviors of SCLC. Depleting MTA1 level may be an effective strategy by which to suppress SCLC growth and metastasis in future biotherapeutic attempts. IntroductionLung cancer is one of the most deadly diseases and ranks first as the cause for cancer-related mortality (1). Small cell lung cancer (SCLC), accounting for ~15% of all lung cancer cases, is a highly aggressive subtype with neuroendocrine properties (2). Currently, for SCLC, there is no effective treatment strategy either through surgery or chemotherapy (3), attributed to its early dissemination and fast development of drug resistance after initiation of chemotherapy (4). The 5-year survival of SCLC patients is as low as 15% or less even after aggressive treatment (5). In light of targeted therapeutic approaches which have shown advantages over traditional strategies, new therapeutic targets must be explored based on the ongoing understanding of molecular mechanisms in lung cancer development and progression.Cancer development and progression are characterized by deregulated gene expression networks which drive the proliferation and metastasis of cancer cells (6). Among the deregulated cancer-related genes, metastasis-associated gene 1 (MTA1) is one of the key players involved in certain steps of cancer development (7). MTA1 is a component of the nuclear remodeling and deacetylation complex (NuRD complex) that affects gene expression ubiquitously (8). MTA1 has been reported to be overexpressed in a series of malignant diseases, including breast cancer (9), esophageal squamous cell carcinoma (10), oral squamous cell carcinoma (11), colon cancer (12) and nonsmall cell lung cancer (NSCLC) (13). Moreover, it has been shown to exert cancer progression in a number of cancer types, such as melanoma, esophageal squamous cell carcinoma and colon cancer, showing promise as a molecular target in cancer therapy strategy development (14). However, whether MTA1 also plays a key role in SCLC malignant behavior or whether it also bears promise in SCLC treatment needs to be ascertained before further potential MTA1-targeted therapeutics can b...

Metastasis-associated protein 1 (MTA1) is a critical component of the nucleosome remodeling and histone deacetylase (NuRD) complex. MTA1 has several biological functions, and it is closely associated with the malignant properties of human cancers; however, the mechanisms and subcellular localization of MTA1 in cells remain unclear. Some initial studies indicated that MTA1 was absent from the nucleolus; however, several NuRD components were recently found to be present in the nucleolus, where they regulate preribosomal RNA (pre-rRNA) transcription. In this study, we demonstrated that MTA1 is definitely localized to the nucleolus and regulates pre-rRNA transcription, which is consistent with the recent reports on NuRD. To determine if MTA1 was present in the nucleolus, we utilized the following complementary molecular approaches: immunofluorescence, GFP-tag tracking, immunoelectron microscopy, and immunoprecipitation (IP). To examine the role of MTA1 in rRNA synthesis, we performed quantitative polymerase chain reaction analysis. We revealed that both endogenous and exogenous MTA1 showed apparent granule-like nucleolar subcellular localization. MTA1 interacts with two major resident nucleolar proteins, nucleolin and nucleophosmin. Immunofluorescent colocalization analyses showed that MTA1 localizes to the fibrillarin-deficient regions of the nucleolus, and Co-IP experiments indicated that there was no interaction between MTA1 and fibrillarin; further, fibrillarin was not identified in the MTA1 interactome. Loss-and gain-of-function studies indicated that MTA1 promotes pre-rRNA transcription in cancer cells. Collectively, our data identify MTA1 as a novel Jian Liu, Chunxiao Li, and Hongsheng Xue contributed equally to this study.