Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
ReviewNFAT as cancer target: Mission possible?
Introduction
The nuclear factor of activated T cells (NFAT) was first described as an inducible nuclear factor binding to the antigen receptor response element-2 (ARRE-2) of the interleukin-2 (IL-2) promoter in human T cells [1], [2]. Subsequent studies revealed that NFAT was not only expressed in T cells, but also ubiquitously expressed in various immune and non-immune cells in the vertebrate systems [3], [4], [5]. Recent studies have further indicated that NFAT plays multiple regulatory roles in cell fate determination, embryonic development, and organogenesis (especially the cardiac, hematopoietic, skeletal, and neuronal systems) [6], [7], [8].
The NFAT family contains five members, including four calcium-responsive isoforms named NFAT1 (NFATc2 or NFATp) [9], [10], NFAT2 (NFATc1 or NFATc) [11], NFAT3 (NFATc4) [12], and NFAT4 (NFATc3 or NFATx) [13], and a tonicity-responsive enhancer-binding protein (TonEBP, also known as NFAT5) [14], [15], [16]. Except for NFAT5, the other members are activated by Ca2 + influx in the cell, either via the PLC-γ pathway or via store-operated Ca2 + entry, typically in T lymphoid cells [17]. The calcium-responsive NFAT isoforms (NFAT1–NFAT4) exist in a hyperphosphorylated state in the cytoplasm [17]. They are usually activated by increased intracellular calcium levels, via dephosphorylation by calcineurin and subsequent nuclear translocation [18], [19], [20]. Once in the nucleus, NFAT1–NFAT4 activate transcription of downstream gene targets, thus directly linking calcium signaling to gene expression [21], [22], [23].
Dysregulation of NFAT signaling is associated with malignant phenotypes and tumor progression [22]. It has been observed that NFAT isoforms are overexpressed and/or constitutively activated in both human solid tumors and hematological malignancies [5], [22], [24]. Indeed, the NFAT transcription factors have been shown to regulate cell survival, differentiation, angiogenesis, invasive migration, and the tumor microenvironment, which will be discussed in the subsequent sections. Therefore, a thorough understanding of NFAT's roles in tumor development and progression will facilitate the development of safe and effective treatment modalities targeting the NFAT pathway in cancer.
In this review, we focus on the recent findings related to the NFAT regulation and their roles in tumor development and progression. In addition, we review various inhibitors of NFAT and the current strategies for targeting the NFAT signaling in cancers.
Section snippets
NFAT biology
All NFAT proteins share a highly conserved Rel-homology domain (RHD) (Fig. 1) [25]. This domain is structurally similar to the DNA binding domain of the nuclear factor-κB (NF-κB) family [26], [27]. As a unifying characteristic in all NFAT proteins, RHD endows the NFAT members with a common DNA-binding specificity [25]. In addition, the calcium-responsive NFAT isoforms (NFAT1–NFAT4) typically have another moderately conserved domain, NFAT homology domain (NHD) (Fig. 1) that binds to promoter
Calcineurin–NFAT signaling pathway
The regulation of the NFAT signaling pathway by calcium and calcineurin has been extensively reviewed [5], [12], [36]. We present here a brief overview of the calcineurin–NFAT signaling pathway, NFAT kinases, and other mechanisms for NFAT regulation, which have also been depicted in Fig. 2. Briefly, in normal, unstimulated cells, NFAT proteins are present in the cytosol in a hyperphosphorylated, inactive form [17], [28], [30]. They are activated by the engagement of cell surface receptors such
The NFAT signaling pathway in cancer development and progression
The wide range of cellular processes controlled by the NFAT proteins and their crucial role in embryonic development, organogenesis, and cell fate determination indicates a strong oncogenic potential for this family of transcription factors. This oncogenic potential of NFAT proteins is further validated by their involvement in the regulation of genes that control cell cycle progression, cell development and differentiation, cell motility, tumorigenesis, and angiogenesis [22]. Moreover, it has
Targeting NFAT for cancer prevention and therapy
Our discussion, so far, has highlighted the crucial importance of NFAT as a regulator of both tumor development as well as progression. Based on their oncogenic potential, the NFAT family seems to be an attractive target for both cancer prevention and therapy. We will discuss the validity of NFAT as a viable chemotherapeutic/chemopreventive target in the following paragraphs.
Future directions and conclusions
Accumulating evidence over the past decade indicates a key role for NFAT transcription factors in diverse pathophysiological states such as inflammation and cancer, apart from their seminal functions in immune surveillance. However, the common feature in all disease states is that the NFAT proteins must be activated in the nucleus and bind to the DNA to cause transcription of its downstream targets. NFAT activity has been shown to be crucial for cell survival and proliferation, invasive
Acknowledgments
This work was supported by NIH grants R01 CA112029, R01 CA121211, and R01 CA186662. This study was also supported by grants from the National Nature Science Foundation (81125020), and the Ministry of Science and Technology of China (2012BAK01B00). The contents of the paper are solely the responsibility of the authors, and do not necessarily represent the official views of the National Institutes of Health. We thank the current and former members of our laboratories for their contributions to
References (212)
- et al.
The role of NFATp in cyclosporin A-sensitive tumor necrosis factor-alpha gene transcription
J. Biol. Chem.
(1994) NF-ATp: a transcription factor required for the co-ordinate induction of several cytokine genes
Immunol. Today
(1994)- et al.
NFAT signaling in vertebrate development
Curr. Opin. Genet. Dev.
(2001) - et al.
Signals transduced by Ca(2 +)/calcineurin and NFATc3/c4 pattern the developing vasculature
Cell
(2001) - et al.
Isolation of two new members of the NF-AT gene family and functional characterization of the NF-AT proteins
Immunity
(1995) - et al.
NFATc3, a lymphoid-specific NFATc family member that is calcium-regulated and exhibits distinct DNA binding specificity
J. Biol. Chem.
(1995) - et al.
Identification of a physical interaction between calcineurin and nuclear factor of activated T cells (NFATp)
J. Biol. Chem.
(1996) - et al.
Calcineurin binds the transcription factor NFAT1 and reversibly regulates its activity
J. Biol. Chem.
(1996) - et al.
NFAT signaling: choreographing the social lives of cells
Cell
(2002) - et al.
A similar DNA-binding motif in NFAT family proteins and the Rel homology region
J. Biol. Chem.
(1995)
NF-AT-AP-1 and Rel–bZIP: hybrid vigor and binding under the influence
Cell
The Rel family of eukaryotic transcription factors
Curr. Opin. Struct. Biol.
Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activity
Mol. Cell
NFATc1 and NFATc2 together control both T and B cell activation and differentiation
Immunity
Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development
Immunity
NFAT control of innate immunity
Blood
Neurotrophins and netrins require calcineurin/NFAT signaling to stimulate outgrowth of embryonic axons
Cell
Isolation of mutant T lymphocytes with defects in capacitative calcium entry
Immunity
Signaling to transcription: store-operated Ca2 + entry and NFAT activation in lymphocytes
Cell Calcium
Selective activation of the transcription factor NFAT1 by calcium microdomains near Ca2 + release-activated Ca2 + (CRAC) channels
J. Biol. Chem.
Calcineurin is a common target of cyclophilin–cyclosporin A and FKBP–FK506 complexes
Cell
Cabin 1, a negative regulator for calcineurin signaling in T lymphocytes
Immunity
NFATc1 mediates HDAC-dependent transcriptional repression of osteocalcin expression during osteoblast differentiation
Bone
Disruption of a nuclear NFATc2 protein stabilization loop confers breast and pancreatic cancer growth suppression by zoledronic acid
J. Biol. Chem.
Regulation of glycogen synthase kinase-3 beta (GSK-3beta) by the Akt pathway in gliomas
J. Clin. Neurosci.
Identification of amino acid residues and protein kinases involved in the regulation of NFATc subcellular localization
J. Biol. Chem.
Intramolecular masking of nuclear import signal on NF-AT4 by casein kinase I and MEKK1
Cell
c-Jun N-terminal kinase (JNK) positively regulates NFATc2 transactivation through phosphorylation within the N-terminal regulatory domain
J. Biol. Chem.
Autoregulation of NFATc1/A expression facilitates effector T cells to escape from rapid apoptosis
Immunity
NFATc1 autoregulation: a crucial step for cell-fate determination
Trends Immunol.
Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts
Dev. Cell
Sumoylation of the transcription factor NFATc1 leads to its subnuclear relocalization and interleukin-2 repression by histone deacetylase
J. Biol. Chem.
A knotty turnabout? Akt1 as a metastasis suppressor
Cancer Cell
Regulation of NFAT by poly(ADP-ribose) polymerase activity in T cells
Mol. Immunol.
Solution structure of the core NFATC1/DNA complex
Cell
Proteolytic regulation of nuclear factor of activated T (NFAT) c2 cells and NFAT activity by caspase-3
J. Biol. Chem.
Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT
Mol. Cell
Inhibition of transcription factor activity by nuclear compartment-associated Bcl-2
J. Biol. Chem.
Involvement of store-operated calcium signaling in EGF-mediated COX-2 gene activation in cancer cells
Cell. Signal.
Characterization of NF(P), the nuclear factor that interacts with the regulatory P sequence (5′-CGAAAATTTCC-3′) of the human interleukin-4 gene: relationship to NF-kappa B and NF-AT
Biochem. Biophys. Res. Commun.
A T cell nuclear factor resembling NF-AT binds to an NF-kappa B site and to the conserved lymphokine promoter sequence “cytokine-1”
J. Biol. Chem.
Integration of Notch 1 and calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control
Dev. Cell
Activation of NFAT signal by p53-K120R mutant
FEBS Lett.
Down syndrome critical region protein 1 (DSCR1), a novel VEGF target gene that regulates expression of inflammatory markers on activated endothelial cells
Blood
Constitutive NF-kappaB and NFAT activation in aggressive B-cell lymphomas synergistically activates the CD154 gene and maintains lymphoma cell survival
Blood
An epigenetic chromatin remodeling role for NFATc1 in transcriptional regulation of growth and survival genes in diffuse large B-cell lymphomas
Blood
Constitutive NF-kappaB and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas
Blood
Promiscuous partnerships in Ewing's sarcoma
Cancer Genet.
Identification of a putative regulator of early T cell activation genes
Science
Characterization of antigen receptor response elements within the interleukin-2 enhancer
Mol. Cell. Biol.
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These authors contributed equally to this work.