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HMGA2 As a Critical Regulator in Cancer Development

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HMGA2 As a Critical Regulator in Cancer Development G C A T T A C G G C A T genes Review HMGA2 as a Critical Regulator in Cancer Development Behzad Mansoori 1,2,3,4 , Ali Mohammadi 1,3, Henrik J. Ditzel 3,5,6 , Pascal H. G. Duijf 7,8 , Vahid Khaze 1,3, Morten F. Gjerstorff 3,5,6,* and Behzad Baradaran 1,* 1 Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran; [email protected] (B.M.); [email protected] (A.M.); [email protected] (V.K.) 2 Student Research Committee, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran 3 Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark; [email protected] 4 Aging Research Institute, Physical Medicine and Rehabilitation Research Center, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran 5 Department of Oncology, Odense University Hospital, 5000 Odense, Denmark 6 Academy of Geriatric Cancer Research (AgeCare), Odense University Hospital, 5000 Odense, Denmark 7 Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4102, Australia; [email protected] 8 University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD 4102, Australia * Correspondence: [email protected] (M.F.G.); [email protected] (B.B.) Abstract: The high mobility group protein 2 (HMGA2) regulates gene expression by binding to AT-rich regions of DNA. Akin to other DNA architectural proteins, HMGA2 is highly expressed in embryonic stem cells during embryogenesis, while its expression is more limited at later stages of development and in adulthood. Importantly, HMGA2 is re-expressed in nearly all human ma- lignancies, where it promotes tumorigenesis by multiple mechanisms. HMGA2 increases cancer cell proliferation by promoting cell cycle entry and inhibition of apoptosis. In addition, HMGA2 Citation: Mansoori, B.; Mohammadi, influences different DNA repair mechanisms and promotes epithelial-to-mesenchymal transition A.; Ditzel, H.J.; Duijf, P.H.G.; Khaze, by activating signaling via the MAPK/ERK, TGFβ/Smad, PI3K/AKT/mTOR, NFkB, and STAT3 V.; Gjerstorff, M.F.; Baradaran, B. pathways. Moreover, HMGA2 supports a cancer stem cell phenotype and renders cancer cells HMGA2 as a Critical Regulator in resistant to chemotherapeutic agents. In this review, we discuss these oncogenic roles of HMGA2 in Cancer Development. Genes 2021, 12, different types of cancers and propose that HMGA2 may be used for cancer diagnostic, prognostic, 269. https://doi.org/10.3390/ and therapeutic purposes. genes12020269 Keywords: β Academic Editor: Félix Machín HMGA2; cancer; cell cycle; apoptosis; DNA repair; MAPK; TGF ; RKIP; miRNA Received: 7 January 2021 Accepted: 8 February 2021 Published: 13 February 2021 1. Introduction High mobility group (HMG) proteins are nonhistone, chromatin-associated molecules Publisher’s Note: MDPI stays neutral involved in maintenance and functional regulation of DNA, including the processes of repli- with regard to jurisdictional claims in cation, recombination, transcription, and DNA repair [1]. The proteins of this superfamily published maps and institutional affil- bend DNA upon binding to the minor groove and thereby contribute to transcriptional regu- iations. lation and maintenance of the chromatin structure [2]. HMG proteins have extremely broad DNA sequence specificity, therefore supplying an exceptional mechanism for protein–DNA interactions [3]. The biological activities of HMG proteins are regulated through epigenetic mechanisms, which affect their interactions with DNA and other transcription factors. Copyright: © 2021 by the authors. Consequently, this affects signaling pathways by recruitment of different transcription Licensee MDPI, Basel, Switzerland. factors to the target gene promotors, which cause a specific phenotypic outcome. This article is an open access article The HMG superfamily is grouped into three main families, including HMGA, HMGB distributed under the terms and and HMGN. The HMGA gene family consists of two functional members, high mobility conditions of the Creative Commons group A1 (HMGA1or HMGI/Y) and high mobility group A2 (HMGA2 or HMGI-C). Attribution (CC BY) license (https:// HMGA proteins bind to AT-rich DNA regions that exist in short stretches in the minor creativecommons.org/licenses/by/ groove of the DNA (Figure1)[ 4]. In addition to DNA, they also interact with different 4.0/). Genes 2021, 12, 269. https://doi.org/10.3390/genes12020269 https://www.mdpi.com/journal/genes Genes 2021, 12, x FOR PEER REVIEW 2 of 23 C). HMGA proteins bind to AT-rich DNA regions that exist in short stretches in the minor groove of the DNA (Figure 1) [4]. In addition to DNA, they also interact with different proteins, such as E2 promoter-binding factor 1 (E2F1) and retinoblastoma protein (Rb). Increasing evidence indicates that HMGA proteins do not directly regulate transcriptional activity, but rather control gene expression by changing chromatin structure and organ- Genes 2021, 12, 269 2 of 23 izing several transcription factors on a so-called “enhanceosome” [5,6]. When HMGA2 binds to AT-rich hooks of DNA, the conformation changes from disordered to ordered, and in turn this introduces bending, unwinding, straightening, and looping of DNA [7]. Theproteins, acidic such tail of as the E2 HMGA2 promoter-binding protein is resp factoronsible 1 (E2F1) for protein–protein and retinoblastoma interactions. protein Thus, (Rb). thisIncreasing domain evidence mediates indicates binding that of HMGA2 HMGA proteins to other do DNA not directlybinding regulateproteins, transcriptional such as tran- scriptionactivity, but factors rather [8]. control gene expression by changing chromatin structure and organizing severalRecent transcription studies suggest factors a on possible a so-called link “enhanceosome”between HMG proteins [5,6]. When and cancer HMGA2 develop- binds mentto AT-rich [9,10]. hooks HMGA2 of DNA, is important the conformation during ea changesrly embryogenesis from disordered and is to highly ordered, expressed and in duringturn this oncogenesis. introduces bending,Studies have unwinding, shown straightening,that HMGA2 andincreases looping cancer of DNA progression [7]. The throughacidic tail the of activation the HMGA2 of several protein pathways. is responsible In this for protein–proteinliterature review, interactions. we highlight Thus, the thison- cogenicdomain role mediates of HMGA2 binding in of tumor HMGA2 development to other DNA and bindingprogression proteins, and discuss such as transcriptionthe probable signalingfactors [8 ].pathways affected by this architectural protein. Figure 1. Schematic of the highFigure mobility 1. Schematic group of protein the high 2 (HMGA2)mobility group gene protein and protein. 2 (HMGA2) Located gene on and chromosome protein. Located 12, the on HMGA2 gene encodes a smallchromosome protein, which12, thecan HMGA2 bind togene AT-rich encodes sites a insmall the pr minorotein, groove which ofcan DNA bind andto AT-rich subsequently sites in the regulate transcription by inducingminor groove conformational of DNA and changes subsequently to the DNA. regulate transcription by inducing conformational changes to the DNA. Recent studies suggest a possible link between HMG proteins and cancer develop- 2.ment HMGA2 [9,10]. Structure HMGA2 isand important Function during early embryogenesis and is highly expressed dur- ing oncogenesis.The HMGA2 Studies gene contains have shown five exons that HMGA2 distributed increases over a cancergenomic progression area of more through than 140the activationkb located ofat severalhuman pathways.chromosome In this12q13-15 literature (Figure review, 1). The we first highlight three theexons oncogenic encode therole AT-binding of HMGA2 indomain tumor site, development while exon and 4 en progressioncodes a protein and discuss linker theand probable exon 5 the signaling acidic domainpathways which affected does by not this activate architectural transcription protein. (Figure 1). HMGA2 is a rather small protein of less than 12 kDa, comprising 108 amino acids. Akin to the other protein family mem- bers,2. HMGA2 HMGA2 Structure regulates and gene Function expression by binding to the DNA minor groove and chro- matinThe management HMGA2 gene [11]. contains five exons distributed over a genomic area of more than 140 kb located at human chromosome 12q13-15 (Figure1). The first three exons encode the AT-binding domain site, while exon 4 encodes a protein linker and exon 5 the acidic domain which does not activate transcription (Figure1). HMGA2 is a rather small protein of less than 12 kDa, comprising 108 amino acids. Akin to the other protein family members, HMGA2 regulates gene expression by binding to the DNA minor groove and chromatin management [11]. The HMGA2 AT-binding domains are each comprised of nine amino acids, including the invariable repeat Arg-Gly-Arg-Pro [12]. During transcription, these domains can bind Genes 2021, 12, x FOR PEER REVIEW 3 of 23 Genes 2021, 12, 269 3 of 23 The HMGA2 AT-binding domains are each comprised of nine amino acids, including the invariable repeat Arg-Gly-Arg-Pro [12]. During transcription, these domains can bind toto B-shaped B-shaped DNA DNA and and convert convert it itfrom from disordered disordered to toordered ordered conformations. conformations. Based Based on the on numberthe number and andlocation location of the of theAT-rich AT-rich binding binding sites,
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