biomolecules Communication Regulation of S100A10 Gene Expression Aleksandra Głowacka 1, Paweł Bieganowski 2 , Ewelina Jurewicz 1 , Wiesława Le´sniak 1 , Tomasz Wilanowski 3,* and Anna Filipek 1,* 1 Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Str., 02-093 Warsaw, Poland; [email protected] (A.G.); [email protected] (E.J.); [email protected] (W.L.) 2 Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawi´nskiegoStr., 02-106 Warsaw, Poland; [email protected] 3 Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 1 Miecznikowa Str., 02-096 Warsaw, Poland * Correspondence: [email protected] (T.W.); a.fi[email protected] (A.F.); Tel.: +48-22-589-23-32 (A.F.); Fax: +48-22-822-53-42 (A.F.) Abstract: S100A10, a member of the S100 family of Ca2+-binding proteins, is a widely distributed protein involved in many cellular and extracellular processes. The best recognized role of S100A10 is the regulation, via interaction with annexin A2, of plasminogen conversion to plasmin. Plasmin, together with other proteases, induces degradation of the extracellular matrix (ECM), which is an important step in tumor progression. Additionally, S100A10 interacts with 5-hydroxytryptamine 1B (5-HT1B) receptor, which influences neurotransmitter binding and, through that, depressive symptoms. Taking this into account, it is evident that S100A10 expression in the cell should be under strict control. In this work, we summarize available literature data concerning the physiological stimuli and transcription factors that influence S100A10 expression. We also present our original results showing for the first time regulation of S100A10 expression by grainyhead-like 2 transcription Citation: Głowacka, A.; factor (GRHL2). By applying in silico analysis, we have found two highly conserved GRHL2 binding Bieganowski, P.; Jurewicz, E.; Le´sniak, sites in the 1st intron of the gene encoding S100A10 protein. Using chromatin immunoprecipitation W.; Wilanowski, T.; Filipek, A. (ChIP) and luciferase assays, we have shown that GRHL2 directly binds to these sites and that this Regulation of S100A10 Gene DNA region can affect transcription of S100A10. Expression. Biomolecules 2021, 11, 974. https://doi.org/10.3390/ Keywords: cancer; gene expression; grainyhead-like 2; S100A10 biom11070974 Academic Editor: Donald Cameron 1. Introduction Received: 18 May 2021 The S100 protein family consists of over 20 low molecular weight (10–12 kDa), Ca2+- Accepted: 28 June 2021 Published: 2 July 2021 binding proteins expressed only in vertebrates [1]. In the human genome, genes encoding 17 members of the S100 family are clustered on chromosome 1 (1q21) [2]. Despite their Publisher’s Note: MDPI stays neutral shared localization, expression of S100 genes is not spatiotemporally synchronized and 2+ with regard to jurisdictional claims in each gene has its own expression pattern [3,4]. S100 proteins bind Ca through two 2+ published maps and institutional affil- “EF-hand” motifs. In a Ca -bound form, they interact with a variety of protein ligands iations. which, in consequence, leads to regulation of numerous processes inside and outside the cell [5,6]. S100A10 is a unique member of the S100 protein family in that it does not bind Ca2+ and is insensitive to changes in Ca2+ concentration. Both “EF hand” motifs in S100A10 have amino acid substitutions that allow them to maintain a conformation, which resembles Copyright: © 2021 by the authors. 2+ Licensee MDPI, Basel, Switzerland. that of other S100 proteins in a Ca -bound form. This means that S100A10 is permanently This article is an open access article locked in an active state [7]. Inside the cell, S100A10 forms a heterotetrameric complex with 2+ distributed under the terms and annexin A2, a protein that binds Ca and phospholipids [8]. The annexin A2-S100A10 conditions of the Creative Commons complex is involved in many membrane-associated processes, e.g., trafficking, fusion, Attribution (CC BY) license (https:// microdomain or lipid raft organization and cytoskeleton-membrane binding. Additionally, creativecommons.org/licenses/by/ this complex binds F-actin, which suggests that it is involved in cytoskeletal reorganization 4.0/). and regulation. Moreover, the annexin A2-S100A10 complex interacts with plasminogen Biomolecules 2021, 11, 974. https://doi.org/10.3390/biom11070974 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, x 2 of 10 Biomolecules 2021, 11, 974 2 of 9 cytoskeletal reorganization and regulation. Moreover, the annexin A2-S100A10 complex interacts with plasminogen and facilitates its conversion into plasmin, a serine protease andthat facilitates is responsible its conversion for fibrinolysis into plasmin, but can also a serine activate protease metalloproteinases that is responsible and degrade for fibri- nolysisextracellular but can matrix also activate (ECM) metalloproteinasesproteins [9]. Dysregulation and degrade of plas extracellularminogen conversion matrix (ECM) to proteinsplasmin [9 plays]. 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FigureFigure 1. 1.Role Role of of S100A10 S100A10 in in tumor tumor progression.progression. 2.2. Regulation Regulation of ofS100A10 S100A10Expression—Literature Expression—Literature Data TheThe gene gene encoding encoding S100A10 S100A10 isis highly highly inducibleinducible andand itsits expressionexpression seemsseems to bebe regu-reg- latedulated by numerousby numerous external external and and internal internal factors. factors. Studies Studies performed performed by different by different research re- groupssearch identifiedgroups identified many physiological many physiological stimuli thatstimuli promoted that promoted S100A10 S100A10 expression, expression, among themamong transforming them transforming growth factor- growthβ (TGF- factor-β), gonadotrophinβ (TGF-β), gonadotrophin (GD), epidermal (GD), growth epidermal factor (EGF),growth basic factor fibroblast (EGF), basic growth fibroblast factor (bFGF),growth interleukinfactor (bFGF), 1β interleukin(IL-1β)[13 ],1β brain-derived (IL-1β) [13], neurotrophicbrain-derived factor neurotrophic (BDNF) [factor15], fibroblast (BDNF) growth[15], fibroblast factor 2 growth (FGF2) fa [16ctor], and 2 (FGF2) nitric oxide[16], (NO)and [nitric17]. Theoreticaloxide (NO) analysis[17]. Theoretical of the S100A10 analysis promoterof the S100A10 identified promoter many identified potential many regu- latorypotential sites, regulatory among them sites,γIRE, among GAS, them and γ GRE,IRE, andGAS, consensus and GRE, binding and consensus sequences binding for the followingsequences transcription for the following factors: transcription AP-1, Sp1, Sp2,factors: NF κAP-1,B, HIF1, Sp1, ATF, Sp2, and NFκ CTF-NF1B, HIF1, ATF, [13]. Overand time,CTF-NF1 the binding [13]. Over of these time, andthe otherbinding transcription of these and factors other totranscription their cognate factors binding to their sites withincognate the binding regulatory sites regions within ofthe S100A10 regulatory has regions been verified of S100A10 experimentally, has been verified providing exper- rele- vantimentally, information providing on the relevant regulation information of S100A10 on expression.the regulation It was of S100A10 proposed, expression. for example, It basedwas proposed, on the effects for example, of siRNA-induced based on the knockdown effects of siRNA-induced of several transcription knockdown factors, of sever- that c-Fosal transcription and c-Jun may factors, act asthat activators, c-Fos and while c-Jun CREM, may act Fosl2, as activators, STAT3, Sp1, while and CREM, SRF may Fosl2, act asSTAT3, inhibitors, Sp1, ofand S100A10 SRF may expression act as inhibitors,