Review
NF-Y in cancer: Impact on cell transformation of a gene essential for proliferation

https://doi.org/10.1016/j.bbagrm.2016.12.005Get rights and content

Highlights

  • CCAAT boxes are overrepresented in gene promoters overexpressed in cancers.

  • NF-Y regulates transcription of genes involved in cellular transformation.

  • Evidence about NF-Y involvement in cancer-associated pathways are reviewed.

Abstract

NF-Y is a ubiquitous heterotrimeric transcription factor with a binding affinity for the CCAAT consensus motif, one of the most common cis-acting element in the promoter and enhancer regions of eukaryote genes in direct (CCAAT) or reverse (ATTGG) orientation. NF-Y consists of three subunits, NF-YA, the regulatory subunit of the trimer, NF-YB, and NF-YC, all required for CCAAT binding. Growing evidence in cells and animal models support the notion that NF-Y, driving transcription of a plethora of cell cycle regulatory genes, is a key player in the regulation of proliferation. Proper control of cellular growth is critical for cancer prevention and uncontrolled proliferation is a hallmark of cancer cells. Indeed, during cell transformation aberrant molecular pathways disrupt mechanisms controlling proliferation and many growth regulatory genes are altered in tumors. Here, we review bioinformatics, molecular and functional evidence indicating the involvement of the cell cycle regulator NF-Y in cancer-associated pathways. This article is part of a Special Issue entitled: Nuclear Factor Y in Development and Disease, edited by Prof. Roberto Mantovani.

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

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,

References (156)

  • R.J. Isaacs et al.

    Regulation of the human topoisomerase IIalpha gene promoter in confluence-arrested cells

    J. Biol. Chem.

    (Jul 12 1996)
  • G. Marziali et al.

    The activity of the CCAAT-box binding factor NF-Y is modulated through the regulated expression of its A subunit during monocyte to macrophage differentiation: regulation of tissue-specific genes through a ubiquitous transcription factor

    Blood

    (1999 Jan 15)
  • A.D. Domashenko et al.

    TAT-mediated transduction of NF-Ya peptide induces the ex vivo proliferation and engraftment potential of human hematopoietic progenitor cells

    Blood

    (Oct 14 2010)
  • Q. Hu et al.

    Stable expression of a dominant negative mutant of CCAAT binding factor/NF-Y in mouse fibroblast cells resulting in retardation of cell growth and inhibition of transcription of various cellular genes

    J. Biol. Chem.

    (2000)
  • R. Mantovani et al.

    Dominant negative analogs of NF-YA

    J. Biol. Chem.

    (12 1994 Aug)
  • G. Bungartz et al.

    NF-Y is necessary for hematopoietic stem cell proliferation and survival

    Blood

    (Feb 9 2012)
  • F. Spallotta et al.

    nitric oxide-dependent cross-talk between class I and III histone deacetylases accelerates skin repair

    J. Biol. Chem.

    (Apr 19 2013)
  • R.A. Currie

    NF-Y is associated with the histone acetyltransferases GCN5 and P/CAF

    J. Biol. Chem.

    (1998)
  • Y. Peng et al.

    The NFY transcription factor inhibits von Willebrand factor promoter activation in non-endothelial cells through recruitment of histone deacetylases

    J. Biol. Chem.

    (Mar 7 2003)
  • S. Di Agostino et al.

    Gain of function of mutant p53: the mutant p53/NF-Y protein complex reveals an aberrant transcriptional mechanism of cell cycle regulation

    Cancer Cell

    (2006 Sep)
  • J. Yun et al.

    Cdk2-dependent phosphorylation of the NF-Y transcription factor and its involvement in the p53-p21 signaling pathway

    J. Biol. Chem.

    (Sep 19 2003)
  • P. Benatti et al.

    Direct non transcriptional role of NF-Y in DNA replication

    Biochim. Biophys. Acta

    (Apr 2016)
  • H. Goodarzi et al.

    Revealing global regulatory perturbations across human cancers

    Mol. Cell

    (Dec 11 2009)
  • K. Yamanaka et al.

    Expression levels of NF-Y target genes changed by CDKN1B correlate with clinical prognosis in multiple cancers

    Genomics

    (Oct 2009)
  • S.C. Lin

    Identification of an NF-Y/HMG-I(Y)-binding site in the human IL-10 promoter

    Mol. Immunol.

    (Mar 2006)
  • S.H. Park et al.

    Transcriptional regulation of the transforming growth factor beta type II receptor gene by histone acetyltransferase and deacetylase is mediated by NF-Y in human breast cancer cells

    J. Biol. Chem.

    (Feb 15 2002)
  • H.T. Zhang et al.

    Activation of PRMT5 by NF-Y is required for cell growth and negatively regulated by the PKC/c-Fos signaling in prostate cancer cells

    Biochim. Biophys. Acta

    (Nov 2014)
  • Y. Wang et al.

    The gene pair PRR11 and SKA2 shares a NF-Y-regulated bidirectional promoter and contributes to lung cancer development

    Biochim. Biophys. Acta

    (Sep 2015)
  • M. Su et al.

    Recruitment of nuclear factor Y to the inverted CCAAT element (ICE) by c-Jun and E1A stimulates basal transcription of the bone sialoprotein gene in osteosarcoma cells

    J. Biol. Chem.

    (Nov 18 2005)
  • Y. Yanagawa et al.

    The transcriptional regulation of human aldehyde dehydrogenase 1 gene

    J. Biol. Chem.

    (1995)
  • H. Xu et al.

    The CCAAT box-binding transcription factor NF-Y regulates basal expression of human proteasome genes

    Biochim. Biophys. Acta

    (Apr 2012)
  • R.A. Mantovani

    Survey of 178 NF-Y binding CCAAT boxes

    Nucleic Acids Res.

    (1998)
  • D. Dolfini et al.

    Perspective of promoter architecture from the CCAAT box

    Cell Cycle

    (2009)
  • J.D. Fleming et al.

    NF-Y coassociates with FOS at promoters, enhancers, repetitive elements, and inactive chromatin regions, and is stereo-positioned with growth-controlling transcription factors

    Genome Res.

    (2013)
  • E. Falcone et al.

    Infinity: an in-silico tool for genome-wide prediction of specific DNA matrices in miRNA genomic loci

    PLoS One

    (Apr 15 2016)
  • D. Dolfini et al.

    Targeting the Y/CCAAT box in cancer: YB-1 (YBX1) or NF-Y?

    Cell Death Differ.

    (2013 May)
  • D.N. Lyabin et al.

    YB-1 protein: functions and regulation

    Wiley Interdiscip. Rev. RNA

    (Jan-Feb 2014)
  • J. Zwicker et al.

    Cell cycle regulation of the cyclin A, cdc25C and cdc2 genes is based on a common mechanism of transcriptional repression

    EMBO J.

    (Sep 15 1995)
  • J. Zwicker et al.

    Cell cycle regulation of cdc25C transcription is mediated by the periodic repression of the glutamine-rich activators NF-Y and Sp1

    Nucleic Acids Res.

    (Oct 11 1995)
  • K.S. Katula et al.

    Cyclin-dependent kinase activation and S-phase induction of the cyclin B1 gene are linked through the CCAAT elements

    Cell Growth Differ.

    (Jul 1997)
  • A. Krämer et al.

    cycA, a CCAAT-binding protein necessary for adhesion-dependent cyclin A transcription, consists of NF-Y and a novel Mr 115,000 subunit

    Cancer Res.

    (Nov 15 1997)
  • F. Bolognese et al.

    The cyclin B2 promoter depends on NF-Y, a trimer whose CCAAT-binding activity is cell-cycle regulated

    Oncogene

    (Mar 11 1999)
  • A. Farina et al.

    Down-regulation of cyclin B1 gene transcription in terminally differentiated skeletal muscle cells is associated with loss of functional CCAAT-binding NF-Y complex

    Oncogene

    (May 6 1999)
  • H. Koessler et al.

    Human replication-dependent histone H3 genes are activated by a tandemly arranged pair of two CCAAT boxes

    Biochem. J.

    (Dec 1 2004)
  • W. Zhu et al.

    E2Fs link the control of G1/S and G2/M transcription

    EMBO J.

    (Nov 24 2004)
  • H.D. Chae et al.

    NF-Y binds to both G1- and G2-specific cyclin promoters; a possible role in linking CDK2/Cyclin A to CDK1/Cyclin B

    BMB Rep.

    (Aug 2011)
  • S. Sciortino et al.

    The cyclin B1 gene is actively transcribed during mitosis in HeLa cells

    EMBO Rep.

    (Nov 2001)
  • R. Elkon et al.

    Genome-wide in silico identification of transcriptional regulators controlling the cell cycle in human cells

    Genome Res.

    (2003)
  • C. Linhart et al.

    Deciphering transcriptional regulatory elements that encode specific cell cycle phasing by comparative genomics analysis

    Cell Cycle

    (2005)
  • M. Grskovic et al.

    Systematic identification of cisregulatory sequences active in mouse and human embryonic stem cells

    PLoS Genet.

    (Aug 2007)
  • Cited by (0)

    This article is part of a Special Issue entitled: Nuclear Factor Y in Development and Disease, edited by Prof. Roberto Mantovani.

    View full text