Metastasis-associated protein 1 inhibits p53-induced apoptosis

Abstract

Abstract. Metastasis-associated protein 1 (MTA1) is highly upregulated in cancer cells with metastatic potential; however, the molecular mechanism by which MTA1 increases the metastatic potential of cancer cells is far from clear. We characterized the functional consequences of MTA1 overexpression on p53-induced apoptosis of cancer cells. MTA1 was associated with p53 in a co-immunoprecipitation assay. MTA1 also had deacetylation activity on p53 in human non-small cell lung cancer cells H1299 and human hepatoma cells SK-Hep1. MTA1 attenuated the transactivation and p21 induction by p53. Moreover, MTA1 expression decreased p53-mediated apoptosis. These results indicate that MTA1 inhibits p53-induced apoptosis by deacetylation of p53, which might be related to the increased metastatic potential of cancer cells with high MTA1 expression. IntroductionMTA1 was originally isolated by differential expression screening of metastatic cell lines with high and low metastatic potentials (1). In vitro studies have shown that MTA1 increases invasiveness and migration (2,3) and suggest that MTA1 may be involved in the regulation of gene expression by covalent modification of histone proteins (4). Consistent with this notion, MTA proteins are physically associated with histone deacetylases (HDAC1/2) and play a role in histone deacetylation and modulation of transcriptional activity as components of the nucleosome remodeling histone deacetylation (NuRD) complex (5). Recent reports have shown that MTA1 enhances angiogenesis by deacetylation and the stabilization of HIF-1α (6,7), providing an important clue in understanding the mechanism of the increased metastatic potential of the cancer cells with high MTA1 expression.Because MTA1 has deacetylating activity, MTA1 may affect the function of other proteins related to cancer progression whose activity is determined by acetylation status. In fact, MTA2, a homologue of MTA1, has been reported to modulate acetylation status and transcriptional activity of p53, while MTA2 has not been linked to metastasis or cancer progression in contrast to MTA1 (8). In response to DNA damage and other types of stress, p53 stabilizes and induces apoptosis, cell-cycle arrest, senescence and differentiation (9,10). Overexpression of p53 activates a number of target genes involved in those processes such as p21CIP1/WAF1, MDM2, GADD45, Cyclin G, Noxa, Bax and PUMA (11-16) through binding to p53 consensus sequences. Therefore, the investigations of the effects of MTA1 on p53 may provide an important clue in understanding the mechanism of the increased metastasis of cancer cells with high MTA1 expression. In this study, we found that MTA1 decreases the transcriptional activity of p53 and inhibits apoptosis through deacetylation of p53. Materials and methodsReagents and antibodies. G418 was purchased from Invitrogen (Carlsbad, CA, USA). Protein G-agarose, protease inhibitor cocktail and FuGENE 6 Reagent were from Roche (Mannheim, Germany). Antibodies to p21, ß-actin and acetylated p53 (Ac-p53) (Lys373, Lys382...

Relationships between metastasis-associated protein (MTA) 1 and lymphatic metastasis in tonsil cancer

“…MTA1 is known to be a component of the ''nucleosome remodeling and histone deacetylation'' (NuRD) complex, which displays histone deacetylase activity. It prevents p53-mediated apoptosis and consequently promotes the metastasis of cancer cells [6]. Moreover, it has been linked with invasion and lymph node metastasis in colon and gastric cancers [4].…”

“…Despite extensive molecular investigations, few reliable biochemical markers for predicting lymphatic metastasis in the head and neck cancers have been identified. Metastasis-associated protein (MTA) 1 has been implicated in invasion and lymph node metastasis in a range of human cancers [3][4][5][6][7]. MTA1 is known to be a component of the ''nucleosome remodeling and histone deacetylation'' (NuRD) complex, which displays histone deacetylase activity.…”

MTA1 downregulation inhibits malignant potential in a small cell lung cancer cell line

“…Cell migration ability was corroborated by a wound healing assay, and the results were further confirmed. Collectively, these findings indicate that inhibition of MTA1 significantly decreased the invasion The MTA1/NuRD complex as a transcriptional co-repressor of tumor suppressors is associated with deacetylated p53 (35,36). p53 was downregulated in the SCLC cell line following MTA1 overexpression, while depletion of MTA1 caused significant apoptosis as detected by flow cytometry and western blotting for cleaved PARP, which is possibly associated with upregulation of PUMA.…”

Involvement of Metastasis Tumor Antigen 1 in Hepatic Regeneration and Proliferation

“…MTA1 had deacetylation activity on p53 in human hepatoma cells SK-Hep1, and MTA1 could inhibit p53-induced apoptosis by deacetylating p53 [8]. Furthermore, activation of the heregulin/HER2 (one of epidermal growth factor (EGF) receptors) pathway can remarkably stimulate the expression of MTA1 and lead to suppression of histone acetylation and enhancement of deacetylase activity [9].…”