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. Author manuscript; available in PMC: 2018 Mar 15.
Published in final edited form as: Lab Invest. 2017 Oct 30;98(2):175–181. doi: 10.1038/labinvest.2017.98

NM23/NDPK proteins in transcription regulatory functions and chromatin modulation: emerging trends

Shalu Sharma 1,2, Antara Sengupta 1, Shantanu Chowdhury 1,2,3
PMCID: PMC5854247  EMSID: EMS75514  PMID: 29083410

Abstract

NM23/NDPK proteins have been studied for their metastasis suppressor role but the molecular pathways involved in this process are not very vivid. Nucleotide binding and kinase activities of NM23 proteins implicated in anti-metastatic effects have been widely studied. In addition to these, transcriptional regulation adds another arm to the versatility of NM23 proteins that together with the other functions may contribute to better understanding of underlying mechanisms. In this review we discuss emerging reports describing the role of NM23 proteins in gene regulation and chromatin modulation in association with other factors or on their own.

The metastasis suppressor gene NME/nm23/NDPK was discovered in 1988 by Steeg et al,1 from the analysis of murine melanoma K-1735 cells based on its differential expression with respect to metastatic potential. The first identified member of the nm23 metastasis suppressor gene family has been extensively studied ever since. Later, in 1991 a close homolog of NM23-H1 that shared >88% sequence identity was found and referred to as NM23-H2.2 Subsequently 10 other homologs of this family were discovered across several other species.3 nm23 gene homologs are found in almost all organisms including eukaryotes, eubacteria as well as archaea,4 the only exception being the Mycoplasma taxon.5 NM23 are multifunctional, ubiquitously distributed hexameric histidine kinases that catalyze phosphate-transfer from nucleloside triposphates to diphosphates via a phosphohistidine intermediate following a ping-pong mechanism.6–10 They are involved in regulating several fundamental cellular processes such as cell proliferation, apoptosis, G-protein signaling, and DNA repair.11–13

Among the human members of the nm23 gene family nm23-H1 and nm23-H2 are widely studied as metastasis suppressors and discussed in several reviews.14–17 The phylogenetic analysis of NM23 family members divided them into two distinct groups.3,12 Group I includes NM23-H1-H4—enzymatically active proteins that are 58–88% identical, whereas group II includes proteins that are enzymatically inactive and more divergent, ie, with 22–44% identity.3,12 Members of the NM23 family are known to be involved in multiple DNA-associated functions including nucleotide binding, nucleoside triphosphate synthesis, cleavage of DNA strands through nuclease activity as well as transcription.12 The kinase-related activities of NM23 proteins including their role in metastasis suppression have been discussed in multiple reviews.6–11 Although studies about the role of NM23 in gene regulation and chromatin-associated changes are relatively more recent, this review will focus on these aspects.

NDPK/NM23 Proteins: Evidence Supporting Role in Transcription

Several lines of evidence implicate the role of NM23 proteins in transcriptional regulation of gene expression. These include first, studies such as those substantiating nuclear localization of NM23 proteins, although they have been reported to lack any nuclear localization signal.18 Not only NM23-H1 and H2 the more frequently studied members of the NM23 family but also NM23-H4 was reported to localize in the nucleus.19 Several reports describe nuclear localization of NM23-H1 and NM23-H2 showing cell cycle-dependent transport of NM23-H1 and H2 proteins from cytoplasm to the nucleus during interphase.18,20,21 In addition, Fujita et al19 also showed nuclear localization of NM23-H4, which was previously understood to be found mainly within mitochondria. Second, multiple reports describe binding of NM23-H1/H2 proteins to the nuclease-hypersensitive element (NHE) region within the promoter of the oncogene c-myc and pdgf-a, resulting in transcriptional activation of c-myc and repression of pdgf-a.22–24 Consequently, the Arg34, Asn-69, and Lys-135 amino-acid residues were reported to mediate NM23-H1 and NM23-H2 DNA binding.25 Interestingly, apart from binding at gene promoters interaction with telomeric DNA was also noted.26,27 Third, apart from direct DNA interactions, NM23 proteins were also reported to regulate expression of multiple genes through other transcription factors and regulatory proteins. For example, NM23-H1 was reported to associate with the Epstein–Barr virus nuclear antigen 3C EBNA3C, estrogen receptor alpha (ERα) and other factors28,29 NM23-H2 was shown to associate with several factors including the cellular nucleic acid binding protein such as CNBP,30 estrogen receptor beta (ERβ)31,32 thereby activating c-myc expression (these are discussed in detail below). Table 1 summarizes these aspects for ready reference.

Table 1. NM23/NDPK proteins carry characteristics of conventional transcription factors.

NM23 proteins and nuclear localization
    NM23-H1 and H2 NM23-H1 and NM23-H2 localize to nucleus mainly in interphase18,20,21
    NM23-H4 Increased nuclear localization was demonstrated on SIRT1 mediated acetylation of NM23-H419
NM23 proteins with DNA-binding potential
    NM23-H2 NM23-H2 binds c-myc promoter purine-rich sequence GGGTGGG22,23
    NM23-H2 and NM23-H1 Involvement of Arg34, Asn-69, and Lys-135 residues in DNA binding25
    NM23-H1 and NM23-H2 Both the isoforms demonstrated to interact with PDGF-A promoter24
    NM23-H1 and NM23-H2 Occupancy on several gene promoters CCR5, CD11b, p53, WT1, ING166
    NM23-H2 Interaction with G-quadruplex DNA in c-myc promoter48
    NM23-H2 and NM23-H1 DNA binding with telomeric ssDNA repeats 26,27
    Maize ZmNDPK1 Interaction with G-quadruplex DNA54
NM23 proteins interact with other regulatory proteins
    NM23-H1 Interaction with EBNA3C and regulation of MMP-9,37 COX2,38 alpha V integrin,39 Necdin;40 interaction of mouse NM23β with YB-1 inhibits gelatinasA expression33
    NM23-H2 Interaction with ERβ and activation of downstream genes31,32,56
    NM23-H1 Interaction with STRAP and repression of TGFβ downstream signaling;41,42 interaction with ERα and repression downstream genes29
    NM23-H2 Interaction with CNBP activates c-myc;30 interaction with APP regulates Alzheimer’s disease progression;57 NME2-PIWIL2 interaction upregulates c-myc55
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NM23-H1 and Transcription Regulation through DNA Binding

The first report of transcription regulatory role was from Kaetzel’s group in 2002 demonstrating NM23-H1 mediated transcriptional repression of the oncogene pdgf-a in HeLa cells.24 NM23-H1 was shown to recognize both, a 5′ distal S1 nuclease-hypersensitive silencer element and a proximal regulatory NHE of the pdgf-a promoter. Interestingly, nuclease activity of NM23-H1 within the promoter of pdgf-a was shown to cleave the 3’ end of both the pyrimindine- and purine-rich strands independent of single or double stranded conformation.24 In 2002, NM23β (rat homolog of NM23-H1) was shown to regulate gelatinase A by binding with the GGGTTT-repetitive sequence within the 40 bp enhancer response element 1 (RE-1) of gelatinase A. Overexpression of nm23β in glomerular mesangial cells was found to outcompete the Y-box protein-1 from the RE-1 binding site resulting in repression of gelatinase A.33 Recently, NM23-H1 was reported to induce expression of the extracellular matrix protein fibronectin mRNA and protein in M14 and 1205LU melanoma cell lines. These results were further confirmed in clinical biopsies of normal skin, benign nevi and also in primary melanomas.34

Gene Regulation by NM23-H1 in Collaboration with other Factors

A substantial body of literature suggests regulation by NM23-H1 that is executed through interaction with other proteins or regulatory factors. Interaction of NM23-H1 with the Epstein– Barr virus protein nuclear antigen 3C (EBNA3C) showed increased NM23-H1 nuclear localization and altered NM23-H1 transcriptional activities that influenced both cellular and viral gene expression. Interestingly, this interaction negatively impacts the function of NM23-H1 in suppressing migration of breast carcinoma and Burkitt’s lymphoma cells in vitro.28,35,36 In 2005, Kuppers et al37 further showed NM23-H1 interaction with EBNA3C resulted in upregulation of matrix metalloproteinase 9 (MMP-9) expression through association with Ap1 and NFκB-binding sites on MMP-9 promoter. This interaction reversed the anti-migratory effect of NM23-H1. NM23-H1 and EBNA3C cooperation was also noted to transcriptionally upregulate cyclooxygenase 2 (COX-2) expression by co-binding to target sequences of transcription factors NFκB and CRE in the COX-2 promoter. NM23-H1 upregulated COX2, whereas EBNA3C alone had no effect on COX-2 expression but contributed to increased COX2 expression when coexpressed with NM23-H1.38

In addition to these, reports also showed that NM23-H1 and EBNA3C regulate alpha V integrin expression independently as well as synergistically by binding different transcription factors. EBNA3C binding to the transcription factor Sp1 upregulates alpha V integrin. On the other hand, NM23-H1 binding to GATA-1 resulted in repression of alpha V integrin. Again, NM23-H1 and EBNA3C when coexpressed negated the repression of alpha V integrin expression mediated by NM23-H1.39 Additional work from the same group showed NM23-H1-EBNA3C interaction to be important for transcriptional suppression of the cellular regulatory factor Necdin. Interestingly, Necdin downregulation rescued downstream suppression of the vascular endothelial growth factor (VEGF) promoter and thereby abrogated antiangiogenic effects.40

Protein–protein interactions through NM23-H1 and its impact on gene regulation were also evident from association of NM23-H1 with ERα, which enhanced binding of ERα with the estrogen response element (ERE). This study demonstrated that NM23-H1 silencing in U2 osteosarcoma and MDA-MB231 breast cancer cells resulted in downregulation of an ERE-harboring reporter plasmid, supporting transcription regulation of ERE-harboring progesterone receptor, Bcl2, cyclin-D1 and cathepsin through NM23-H1 However, other ERE-containing genes like pS2 remained unaltered by NM23-H1 levels.29

Interaction of NM23-H1 with the serine threonine kinase receptor associated protein (STRAP) was reported to transcriptionally repress PAI-1, p21 and SMAD7 together with activation of CDK4 and cyclin-D1. These together were shown to repress the downstream TGFβ signaling.41 The same group also reported NM23-H1-STRAP association, following genotoxic stress, with p53 using cystein residues in the central DNA-binding domain (DBD) of p53. Through this interaction NM23-H1-STRAP was found to regulate p53-mediated transcription of apoptosis and cell cycle-related proteins42

NM23-H1—Role in Global Gene Regulation

In addition to studies showing involvement of NM23-H1 in gene regulation either directly or in association with other factors several global studies revealed differential mRNA expression following altered NM23-H1 expression. Microarray analysis performed on oral squamous cell carcinoma cells CAL27 after subjecting them to NM23-H1 overexpression observed 241 genes with change of more than or equal to twofold, 103 of these genes were downregulated, whereas 138 showed upregulation.43 The altered genes were primarily related to cell adhesion, invasion, and metastasis including TGFβ signaling. In another study on transfection of breast cancer MDA-MB-435 cells with nm23-H1, 197 genes were found to be significantly upregulated, whereas the expression of 1961 genes were downregulated.44 Functional significance of the altered genes showed them to cluster into six categories namely, invasion and metastasis, apoptosis and senescence, signal transduction and transcription factors, cell cycle and repair, adhesion, and angiogenesis.

Horak et al45 compared the expression profiles following NM23-H1 overexpressing with cells overexpressing NM23-H1 mutants P96S and S120G that are incapable of inhibiting motility and invasion in breast cancer cells. This study reported nine genes (MET, FZD1, PTN, SMO L1CAM, NETO2, CTGF, MMP-2, and EDG2) downregulated by the wild-type NM23-H1 that remained unaltered in case of NM23-H1 mutants. A later transcriptome analysis in L9981 lung cancer cells showed similar observations.46 L9981-nm23-H1 stable cells characteristically exhibited lower cell proliferation, increased apoptosis and a dramatic loss of tumor cell metastasis. This study emphasized the finding that genes like E-cadherin, b-catenin and TIMP-1 were upregulated, whereas MMP-2, CD44v6, and VEGF were repressed on NM23-H1 overexpression, suggesting altered expression of these genes to be significant in the anti-metastatic function of NM23-H1.

DNA Binding by NM23-H2 and Transcriptional Regulation of Gene Expression

Transcriptional activation of the c-myc oncogene by NM23-H2 was shown in human as well as murine cells, in cervical, lung carcinoma, and Burkitt lymphoma by multiple research groups.16,22,47,48 Furthermore, it was found that NM23-H2 associates with the c-myc promoter NHE, constituting an asymmetric repetitive sequence that is cytosine-rich in one strand and guanine-rich in the other—an arrangement conducive to formation of specific DNA secondary structures called G-quadruplexes.23,49–51 Later, it was shown that NM23-H2 interacts with the c-myc promoter in a manner that was dependent on formation of the G-quadruplex structure.48 Despite these, reports have cast doubt on transcriptional activity of NM23-H2 because of non-specific binding to single-stranded purine-rich sequence.52,53 On the other hand, it is possible that NM23-H2 association to DNA depends on the structure adopted by such sequences rather than mere sequence. In 2015, in maize nucleoside diphosphate kinase1 (ZmNDPK1) the first plant G-quadruplex-binding protein was reported. It is a close homologue of NM23-H2, which was shown to bind folded G-quadruplex structures with higher affinity as compared to unfolded G-rich DNA. The G-quadruplex-binding activity of ZmNDPK1 was demonstrated to be independent of its nucleotide binding and kinase activities.54

Gene Regulation by NM23-H2 in Association with other Factors

Recently, a NM23-H2-interacting protein was reported in relation to c-myc regulation, which supported earlier studies of NM23-H2-G-quadruplex binding in the c-myc promoter. Piwi-like RNA-mediated gene silencing 2, PIWIL2 interaction with NM23-H2 was found to upregulate c-myc expression by facilitating the association of NM23-H2 with the G-quadruplex motif.55 In addition to these, CNBP was shown to interact with NM23-H2 and regulate c-myc expression. It was further demonstrated that CNBP binds to the G-quadruplex structure formed in the NHE region within the c-MYC promoter and while CNBP repressed c-MYC, CNBP-NM23-H2 interaction resulted in upregulation of c-MYC expression.30

As noted for NM23-H1, NM23-H2 also mediated negative regulation of pdgf-a transcription by interacting with its silencer sequence (5′-S1 nuclease-hypersensitive site) along with basal NHE. On transient transfection of NM23-H2 negative regulation of the pdgf-a basal promoter was found in HepG2 cells.24 In addition to these, Rayner et al31 demonstrated association of NM23-H2 with the ERβ.32 Interestingly, in contrast to NM23-H1, which associates with estrogen receptor alpha and functions as a repressor in a estrogen dependent manner, NM23-H2 was found to activate gene expression.31,32,56

In 2013, regulation of the alzheimer associated amyloid-β peptide (APP) was found to be through interaction of NM23-H2 to the proximal regulatory element (PRE) within the APP promoter. Presence of the 30 nucleotide PRE sequence was reported to make APP regulation vulnerable to epigenetic modifications. This report further implicated an increased risk of Alzheimer’s disease on any interference with NM23-H2’s role in regulation of APP.57

Genomic Studies on NM23-H2-Mediated Gene Regulation

In 2014, gene expression profiling along with promoter occupancy of NM23-H2 in lung carcinoma A549 cells was reported.58 Authors found occupancy of NM23-H2 within promoters of 346 genes related to focal adhesion, nucleosome remodeling, transcriptional regulation, apoptosis, Notch signaling pathway, p53, and Wnt signaling pathways. Of these, 64 gene targets also showed altered expression, either up or downregulation, on changing NM23-H2 levels in the cell. Several targets, for example, adenomatous polyposis coli (APC), Rho-related GTP-binding protein B (RHO B) and connective tissue growth factor (CTGF) were found to be under direct regulation of NM23-H2. The study thereafter focused on NM23-H2-mediated transcriptional repression of the focal adhesion factor vinculin (VCL). NM23-H2 was shown to bind a 12-mer motif located 262 bases upstream of vinculin transcription start site.58

In a later more extensive study, genome-wide chromatin-immunoprecipitation followed by sequencing (ChIP-seq) was performed in A549 cells and NM23-H2 target sites were checked before and after induction of nm23-H2.59 A 12-mer consensus motif was identified for NM23-H2 binding, which was present in >70% of the ChIP-seq peaks—a motif that was similar to the one reported by Postel et al within the c-myc promoter NHE several years earlier.23,58 This further revealed 2005 and 11017 peaks in endogenous and induced states respectively. On analyzing the altered gene expression profile 1679 genes were found to be differentially expressed in NM23-H2 altered conditions, 781 genes were upregulated, whereas 898 were downregulated. Of these 1679 gene targets, 1235 genes were found to have at-least one NM23-H2-binding site within 10 kb of the transcription start site.59

A study that described genes differentially expressed in drug resistance cancer cells implicated NM23-H2 as a factor that altered expression of several well known genes involved in epithelial to mesenchymal transition.60 Based on this analysis it was tested and found that NM23-H2 repressed several mesenchymal cell markers (such as SNAI2, VIM, FN1, TIMP-1, ITGA5) while inducing expression of epithelial cell markers (OCLN, CDH1, DSP, PPDE2), thereby promoting mesenchymal to epithelial transition of breast cancer cells (MDA-MB-231). Furthermore, the study reported NM23-H2 levels to be important for preventing drug resistance in cancer cells. Overall, this also supported function of NM23-H2 as a metastasis suppressor.60

NM23-H1 and NM23-H2-Mediated Chromatin Level Changes

Interaction of NM23-H1 with the chromatin remodeling SET complex was reported in 2003 by Fan et al.61 The SET complex is a multimeric 270–420 KDa complex, comprising HMGA, SET, Ape-1, and pp32, generally linked to the chromatin-associated processes of nucleosome assembly, replication, and DNA repair.61 On activation by granzyme A, NM23-H1 as a part of this complex was shown to induce DNase activity thereby inducing cellular apoptosis through chromatin degradation.61 In another study, both NM23-H1 and NM23-H2 were found to be part of a multi-component OCA-S (Oct-1 co-activator complex in S phase) complex in transcriptional activation of the histone 2B gene in a S phase-dependent manner.62 Although both NM23-H1 and NM23-H2 were found to have occupancy on histone 2B gene promoter, their exact role within OCA-S was not clear. This further implicated the significance of NM23 proteins in chromatin modification through regulation of a core histone protein.

More evidence supporting involvement of NM23 in chromatin remodeling was reported in 2014. In a genome-wide ChIP-seq study, NM23-H2 was used as a candidate for testing whether transcription factor binding on target gene promoters influence nucleosome occupancy in its vicinity.59 Using lung cancer A549 cells, authors showed that on induction of NM23-H2, 70% of the putative NM23-H2 binding sites earlier occupied by nucleosomes became nucleosome-free. Perhaps more importantly, it was also shown that these newly vacated sites were occupied by NM23-H2, in the induced cells, resulting in altered expression of the target gene.59

In another study, a yeast two-hybrid screen found NDPK-D (NM23-H4) associates with the NAD+ dependent histone deactylase SIRT1. Here it was also shown that deacetylation by SIRT1 enhances the nuclear localization of NM23-H4. Since no evidence of any specific intra-nuclear functions of NM23-H4 has been revealed as yet it would be interesting to explore its role, if any, in gene regulation particularly due to its interaction with the nucleosome remodeler SIRT1.19

Transactivation Domain in NM23 Proteins: Differing Views

In the light of transcriptional roles attributed to NM23 proteins, particularly NM23-H1 and H2, the differing views on whether they harbor transactivation domain(s) is of interest. NM23-H2 was first implicated in c-myc transactivation in 1995, but a distinct transactivator domain was not defined.22 In 1997, presence of a typical transactivation domain was negated by Michelloti et al,63 when following reporter assays that fused a DBD with wild-type NM23-H2, authors did not observe any transactivation. In the following year, Chae et al64 reported presence of transactivation domain from studies where human nm23-H1 gene constructs were transfected in yeast. They co-transfected a fusion protein containing GAL4/LEXA DBD with a truncated versions of NM23-H1 and noted that the C-terminal residues of NM23 displayed clear transactivation potential, whereas no transactivation was observed through the N-terminal residues. Presence of a C-terminal transactivation domain was further substantiated later when transactivation activity of C-terminal residues of NM23-H1 (amino-acid 109–152) was found in yeast, HeLa, and COS cells.65 Interestingly it was noted that further extension of the domain (including amino acids from 58–152) lead to a loss of transactivation. Authors also tested the role specific mutants—C-terminal residues such as P96S, S120G/S120A (known to inhibit anti-metastatic effect of wild-type NM23-H1) and H118F (NDP Kinase mutant of NM23-H1). Interestingly, only H118F showed reduction of transactivation activity suggesting a link between NDP kinase activity and transactivation potential NM23-H1. In another study, reporter assays in 293T cells using NM23-H1 fused to Gal4 DBD authors found increase in reporter expression.28

Emerging Trends and Future Perspective

Research on regulation of gene expression by NM23 proteins themselves or in collaboration with other interacting partners was primarily discussed here. This, in addition to, the emerging work on involvement of NM23 in chromatin-related processes projects interesting line of work that has received relatively less attention. Also, several genome-wide studies have revealed the global impact of NM23-H1/H2 on a wide array of cellular processes including cell development, differentiation, and proliferation.

We particularly take note of the work that may link the inherent NDP kinase activity of NM23 to its role in gene expression based on the study that found loss of transactivation potential in the mutant NM23-H1 (H118F) devoid of kinase activity.65 Another interesting theme that may open up new avenues comes from the implicated involvement of NM23-H2 in modulating the state of regulatory chromatin through nucleosome repositioning within gene promoter.60 Based on these, future work on the influence of the NDP kinase activity in chromatin modifications, and mechanisms of how this impacts global gene regulation could be of much interest and impact.

Acknowledgments

This work was supported by the Wellcome Trust/DBT India Alliance Fellowship [grant number 500127/Z/09/Z] awarded to SC. Authors acknowledge all Chowdhury-Lab members for their support and critical appreciation. SC is a Senior Fellow of the Wellcome Trust/DBT India Alliance.

Footnotes

Disclosure/Conflict of Interest

The authors declare no conflict of interest.

References

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