Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
ReviewNF-Y in cancer: Impact on cell transformation of a gene essential for proliferation☆
Introduction
The CCAAT-binding transcription factor NF-Y is a heteromeric protein composed of three subunits, NF-YA, NF-YB, and NF-YC, all necessary for CCAAT-binding. NF-YB and NF-YC tight association is a prerequisite for NF-YA binding and sequence-specific DNA interactions. NF-YA contains a Q-rich transcriptional activation domain at the N-terminus, whereas its DNA binding domain and the regions of interaction with NF-YB and NF-YC are located at its C-terminal portion. NF-YA has two major isoforms: NF-YA long (NF-YAl) and NF-YA short (NF-YAs) which lacks 28 amino acids coded by exon 3 within the Q-rich transactivation domain (Fig. 1). Both NF-YB and NF-YC contain putative histone fold motifs and NF-YC has a Q-rich transactivation domain at its C-terminus [1], [2], [3]. The CCAAT motif is present in a plethora of eukaryotic promoters and in accordance with the widespread presence of CCAAT boxes, NF-Y subunits are extremely conserved and have been identified in several eukaryotic kingdoms [1]. All nucleotides of the pentanucleotide are critical for NF-Y binding. However, flanking sequences of the invariably conserved CCAAT core box are also important for it, [4], [5], [6], [7]. Other proteins have been described to be able to bind CCAAT boxes. For instance, in the past, two transcriptional factors (C/EBP and CTF/NF1) have been associated with CCAAT sites. However, several studies have later demonstrated that these two factors have different sequence specificities [8]. Similarly, the RNA binding protein YB-1 have been associated to CCAAT boxes, based on its ability to interact in vitro with CCAAT-box carrying oligonucleotides. However, ChIP-Seq experiments could not reveal YB-1 specificity to CCAAT-boxes. It has been proposed that YB-1 doesn't even bound DNA but newly synthesized mRNA [9]. Thus, the evidences present in literature so far, allow as to speculate that the majority, if not all, CCAAT boxes are bound by NF-Y.
NF-Y binds to and regulates transcription of numerous cell cycle regulatory genes, thus playing a fundamental role in proliferation. Appropriate cellular growth and proliferation exert pivotal roles in many physiological processes. Transcriptional networks control critical circuits governing the maintenance of the cell cycle. Indeed, the appearance of cancer is often preceded by the presence of focal lesions due to aberrant cell proliferation (iperplasia, polyps, adenomas, papillomas, etc.). In agreement, alterations or loss of critical components of transcriptional networks have been found to be associated with cancer [10]
Here, after a description of the role of NF-Y on cell cycle regulation, we review direct and indirect evidence of the impact of NF-Y activity on cell transformation. We will summarize genome wide studies identifying the CCAAT box as over-represented in promoters of genes overexpressed in diverse types of cancers and how some clinical studies indicate that patients with up-regulated expression of NF-Y target genes have poor prognosis in several types of cancer. We will describe how NF-Y regulates transcription of genes highly expressed and/or involved in cellular transformation and how its impact on cell transformation relies on its ability to interact with oncogene or tumor suppressor transcription factors.
Section snippets
NF-Y and cell cycle regulation
In proliferating cells, NF-Y supports the basal transcription of a class of regulatory genes responsible for cell cycle progression, among which are E2F1, cyclin A, cyclin B1, cyclin B2, cdk1, chk2, cdkn1c, cdc25A, cdc25C, dihydro-folate reductase (dhfr), histones, heat shock proteins (HSPs), proliferating cell nuclear antigen (PCNA) and topoisomerase IIα (TopIIα) [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24]. In agreement with this, in silico studies point
CCAAT-boxes and NF-Y binding are enriched on cancer-associated promoters: evidence from bioinformatics tools and molecular biology genome wide approaches
Systematic expression profile approaches indicate that a plethora of NF-Y targets are upregulated in different types of cancer. In this section we will summarize studies that, analyzing global regulatory perturbations across human cancers, point at NF-Y as one of the transcription factors responsible for oncogenic aberrant transcriptional programs.
The first database comprising promoters that contain a bona fide NF-Y binding site was organized in 1998. This survey, based on the evidence coming
NF-Y regulates transcription of genes involved in cellular transformation
The hallmarks of cancer comprise eight biological capabilities acquired during the multi-step development of human cancer, all of them needed for tumor development. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism, and avoiding immune destruction. Moreover, genome instability and tumor-promoting inflammation are able to
NF-Y-interacting partners: p53 and the others
NF-Y plays a fundamental role in proliferation and its perturbations are involved in the pathogenesis of cancer. To mediate its function, NF-Y cooperates with specific proteins among which transcriptional factors and cofactors able to modulate its activity. Depending on these interactions NF-Y may serve as either an activator or a repressor in the transcriptional regulation of target genes.
An example of how NF-Y partners can modulate its ability to activate or repress transcription is the
NF-Y as a target of anti-cancer drugs
Based on the concept that NF-Y regulates transcription of a multiple genes involved in cell transformation, several efforts have been made to inhibit NF-Y transcription activity as an anti-cancer strategy.
One of the first example of a compound that inhibits the binding of NF-Y to DNA dates back to 1999 when Bonfanti and coworkers described the ability of the ecteinascidin-743 (alias ET-743, Yondelis, Trabectedin), a tetrahydroisoquinoline alkaloid isolated from Ecteinascidia turbinate, to
Conclusions and perspectives
Uncontrolled proliferation is one of the hallmarks of cancer and altered expression and/or activity of cell cycle regulatory genes is common in this disease. Therefore identifying molecules that play a key role in controlling proliferation and studying their mechanisms of action during transformation is an attractive field of research for possible therapeutic treatments in cancer. So far, a large volumes of studies has provided findings demonstrating that cancer-specific driving nodes???? are
Transparency Document
Acknowledgements
We thank Silvia Soddu for interesting discussions on and critical reading of the manuscript and Tania Merlino for critical reading of the manuscript. We wish to thank members of the lab that, over the past years, have contributed to NF-Y studies. In particular, Andrea Farina, Paola Fuschi, Selvaggia Sciortino, Silvia D'Agostino, Frauke Goeman, Velia Emiliozzi, Giacoma Simonte, Simona Artuso and Emmanuela Falcone. We also thank our collaborators on NF-Y studies over the years: Roberto Mantovani,
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This article is part of a Special Issue entitled: Nuclear Factor Y in Development and Disease, edited by Prof. Roberto Mantovani.