ReviewMTA1 expression in human cancers – Clinical and pharmacological significance
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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2022, Journal of King Saud University - ScienceCitation Excerpt :MTA1-NuRD complex overexpression stimulates breast invasive carcinoma to metastasis through transcriptional regulation of oncogenes by chromatin remodeling process (Sen et al., 2014). MTA1 regulates both co-activator and co-repressor activities for oncogenes regulation due to the specific association of the NuRD complex (Malisetty et al., 2017). MTA1 overexpression caused quantitative accumulation in the tumor microenvironment that reduces the effects of therapeutic regimes (Liu et al., 2020).
O-GlcNAc modification regulates MTA1 transcriptional activity during breast cancer cell genotoxic adaptation
2021, Biochimica et Biophysica Acta - General SubjectsCitation Excerpt :Through its interaction with diverse components of the NuRD chromatin-remodeling complex, MTA1 can act as both a coactivator and corepressor to regulate target gene transcription. Additionally, MTA1 is a stress-responsive gene, and its accumulation in cancer cells has been linked with the resistance to multiple therapeutic agents, including genotoxicity-inducing drugs [6,8]. Despite the intensive study on MTA1, the mechanism by which MTA1 modulates genotoxic adaptation and promotes tumor progression has not been clearly demonstrated.
Upregulation of circ-UBAP2 predicts poor prognosis and promotes triple-negative breast cancer progression through the miR-661/MTA1 pathway
2018, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Consistently, we also found that miR-661 was markedly decreased in TNBC tissues and that patients with low miR-661 expression exhibited an unfavourable prognosis. MTA1, a well-known oncogene, has been shown to be involved in numerous tumour biological behaviours, including proliferation, apoptosis, migration, invasion, and senescence, etc [35,36]. A previous study demonstrated that MTA1 was negatively regulated by miR-661 in breast cancer [22].
The Roles of Zinc Finger Proteins in Colorectal Cancer
2023, International Journal of Molecular SciencesCRISPR/Cas9 knockout of MTA1 enhanced RANKL-induced osteoclastogenesis in RAW264.7 cells partly via increasing ROS activities
2023, Journal of Cellular and Molecular Medicine