Elsevier

Biomedicine & Pharmacotherapy

Volume 95, November 2017, Pages 956-964
Biomedicine & Pharmacotherapy

Review
MTA1 expression in human cancers – Clinical and pharmacological significance

https://doi.org/10.1016/j.biopha.2017.09.025Get rights and content

Abstract

Remarkably, majority of the cancer deaths are due to metastasis, not because of primary tumors. Metastasis is one of the important hallmarks of cancer. During metastasis invasion of primary tumor cells from the site of origin to a new organ occurs. Metastasis associated proteins (MTAs) are a small family of transcriptional coregulators that are closely associated with tumor metastasis. These proteins are integral components of nuclear remodeling and deacetylation complex (NuRD). By virtue of being integral components of NuRD, these proteins regulate the gene expression by altering the epigenetic changes such as acetylation and methylation on the target gene chromatin. Among the MTA proteins, MTA1 expression is very closely correlated with the aggressiveness of several cancers that includes breast, liver, colon, pancreas, prostate, blood, esophageal, gastro-intestinal etc. Considering its close association with aggressiveness in human cancers, MTA1 may be considered as a potential therapeutic target for cancer treatment. The recent developments in its crystal structure further strengthened the idea of developing small molecule inhibitors for MTA1. In this review, we discuss the recent trends on the diverse functions of MTA1 and its role in various cancers, with the focus to consider MTA1 as a ‘druggable’ target in the control of human cancers.

Introduction

Cancer is a disease of a mass of mutated cells which undergo uncontrollable cell divisions. As mentioned in the book ‘The Emperor of All Melodies-A Biography of Cancer’-by Siddartha Mukharjee, cancer is an uncommited crime. Every year, millions of people around the world die of various cancers. Approximately, 1,685,210 new cases were diagnosed and 595,690 deaths were registered duing 2016 in USA [1]. Remarkably, large number of cancer deaths are due to metastasis, and not because of the primary tumors. Metastasis is therefore one of the important hallmarks of cancer [2]. During metastasis, invasion of primary tumor cells from the site of origin to a new organ occur establishing the malignant tumor at distant location. Size of the tumor appears to be one of the critical factor for tumor metastasis. As the tumor size exceeds 1 cm, these tumor cells tend to metastasize to the secondary sites. Typically, metastasis involves the detachment of primary epithelial cancer cells by loss of E-cadherin, an epithelial marker, resulting in acquisition of mesenchymal phenotype, a process known as epithelial to mesenchymal transition (EMT) [3]. After detaching from the primary tumor through EMT, the disseminated cells enter the blood circulation through cell migration and invasion followed by intravasation. The circulating tumor cells enter the secondary site through extravasation and acclimatizes with the tissue to establish metastasis (Fig. 1). Establishment of secondary tumor is dependent on multiple factors and each primary tumor exibits tissue trophism. For instance, breast tumors are known to metastasize into specific tissues in the order of priority: bone, liver, lung and brain. Given the importance, identification and charactarization of the regulators of tumor metastasis and more importantly, understanding the molecular mechanisms and pathways involved in this critical process is crucial to consider them as potential targets for controlling cancer. In this review, we consider MTA1 has the potential to be considered as a druggable target in cancers.

Section snippets

Identification of MTA1 as tumor associated protein

Since increased mortality and morbidity in cancer patients is primarily due to tumor metastasis, identification and characterization of genes responsible for tumor metastasis is the focus of several laboratories around the world. In 1994, Nicolson laboratory at MD Anderson Cancer Center, USA made such an attempt to identify the metastasis associated genes in breast cancer. This group identified metastasis-associated gene 1 (MTA1), a gene that is harboured on chromosome 14q32.3 in humans, as a

NuRD complex – structure and functions

Gene transcription is a tightly regulated molecular process that provides a different RNA repertoire at different developmental stages to perform specific cellular functions. Various chromatin associated protein complexes that perform activities like DNA binding and histone modification are reported to control the gene transcription [14]. The NuRD complex is one such protein complex that regulates the gene transcription through chromatin compaction and decompaction mechanism [15]. It is a 1 MDa

MTA1 structure and function

In the MTA family, there are three genes which encode three distinct MTA proteins namely MTA1, MTA2 and MTA3, and also the alternative splicing products: MTA1s, MTA1zg29p and MTA3L [15]. All three MTA proteins have highly conserved domains: a Bromo Adjacent Homology domain (BAH), an Egl 27 and MTA1 homology domain (ELM), a SANT domain and a GATA domain (Fig. 3). The functional significance of these domains are to be fully understood with respect to MTA protein functioning within NuRD complex.

Regulation of MTA1 gene expression

In breast cancer cells, MTA1 expression is induced by heregulin β1, interacts with ERα and represses estrogen-dependent transcriptional activation of ERα [13], [16]. MTA1 was also shown to be induced by c-MYC transcriptional factor and is required for c-MYC-dependent cellular transformation [40]. Metabolic stress like hypoxia also induces MTA1 expression in breast cancer cells. Under hypoxia, MTA1 is responsible for HIF1α stabilization and tumor metastasis by up regulating vascular endothelial

MTA1 interacting proteins

Other than NuRD components, MTA1 has large number of regulatory proteins that are involved in various signaling pathways [49]. By interacting with MAT1, LMO4, MICoA, NRIF3, MTA1 was shown to modulate ERα signaling in breast cancer cells [50], [51], [52], [53]. Similarly MTA1 has been shown to regulate DNA damage response signaling by interacting with p53, ATR, COP1, etc [49], [54], [55]. In the context of metastasis, MTA1 was shown to interact with STAT3 pathway to regulate EMT process, a

MTA1 overexpression and cancer

Abundant clinical data on MTA1 expression suggest MTA1 as a molecular marker in various solid tumors [49], [57]. MTA1 expression is significantly correlated with the stage of the cancer defined by local invasiveness and lymph node metastasis [6], [7]. Importantly nuclear expression of MTA1 was found to be associated with tumor grade, angiogenesis and high risk of recurring breast cancer [58]. Recently reports suggested that transcription factor AP2γ (TFAP2c) and IFNγ inducible protein 16

Is MTA1 a druggable target in cancer?

The concept of “Druggability” has continued to evolve in the post genomic era. Although, there is confusion associated with categorizing “druggable” targets and “drug like” molecules on the basis of past success stories, we can say that no target is “undruggable” [111], [112]. Till-today, there is no information about drugs which could affect MTA1 by directly binding to it. However, since MTA1 is part of the NuRD complex which also contains histone deacetylases 1 and 2 (Fig. 2), one approach is

Conclusions and future prospects

Considering various clinical reports demonstrating the importance of MTA1 expression in a variety of human cancers, it is plausible that MTA1 represents an important regulatory protein involved in the progression of aggressive tumors. Furthermore, several clinical studies showed MTA1 expression is associated with advanced tumors, and MTA1 may be useful in the prognosis of patients with these cancers. Screening of chemical libraries using bioinformatics tools to be carried out to identify the

Conflict of interest

The authors declare no conflict of interest to disclose.

Acknowledgments

Authors thank BM lab members for helpful discussions. The research work to BM lab is supported by the Department of Biotechnology (DBT), India grants No- BT/MED/30/SP11273/2015; BT/PR8764/MED/97/104/2013, BT/PR7672/BRB/10/1173/2013; Department of Science and Technology (DST) grant No- SB/SO/BB/013/2013, India (to BM).

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