cells Review Retinoic Acid and Its Derivatives in Skin Łukasz Szyma ´nski 1, Rafał Skopek 1, Małgorzata Palusi ´nska 1, Tino Schenk 2,3, Sven Stengel 4, Sławomir Lewicki 5,6,* , Leszek Kraj 7 , Paweł Kami ´nski 8 and Arthur Zelent 1,* 1 Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Science, Post˛epu36A, 05-552 Magdalenka, Poland; [email protected] (Ł.S.); [email protected] (R.S.); [email protected] (M.P.) 2 Department of Hematology/Oncology, Clinic of Internal Medicine II, Jena University Hospital, 07747 Jena, Germany; [email protected] 3 Institute of Molecular Cell Biology, Center for Molecular Biomedicine Jena (CMB), Jena University Hospital, 07747 Jena, Germany 4 Department of Internal Medicine IV, Division of Gastroenterology, Hepatology and Infectious Disease, Jena University Hospital, Friedrich Schiller University of Jena, 07747 Jena, Germany; [email protected] 5 Department of Regenerative Medicine and Cell Biology, Military Institute of Hygiene and Epidemiology, 01-163 Warsaw, Poland 6 Department of Medicine, Faculty of Medical Sciences and Health Sciences, Kazimierz Pulaski University of Technology and Humanities, 26-600 Radom, Poland 7 Department of Oncology, Medical University of Warsaw, 01-163 Warsaw, Poland; [email protected] 8 Department of Gynecology and Oncological Gynecology, Military Institute of Medicine, 01-163 Warsaw, Poland; [email protected] * Correspondence: [email protected] or [email protected] (S.L.); [email protected] (A.Z.); Tel.: +48-261-816-108 (S.L.); Fax: +48-261-816-141 (S.L.) Received: 27 October 2020; Accepted: 7 December 2020; Published: 11 December 2020 Abstract: The retinoids are a group of compounds including vitamin A and its active metabolite all-trans-retinoic acid (ATRA). Retinoids regulate a variety of physiological functions in multiple organ systems, are essential for normal immune competence, and are involved in the regulation of cell growth and differentiation. Vitamin A derivatives have held promise in cancer treatment and ATRA is used in differentiation therapy of acute promyelocytic leukemia (APL). ATRA and other retinoids have also been successfully applied in a variety of dermatological conditions such as skin cancer, psoriasis, acne, and ichthyosis. Moreover, modulation of retinoic acid receptors and retinoid X (or rexinoid) receptors function may affect dermal cells. The studies using complex genetic models with various combinations of retinoic acid receptors (RARs) and retinoid X (or rexinoid) receptors (RXRs) indicate that retinoic acid and its derivatives have therapeutic potential for a variety of serious dermatological disorders including some malignant conditions. Here, we provide a synopsis of the main advances in understanding the role of ATRA and its receptors in dermatology. Keywords: vitamin A; all-trans-retinoic acid; retinoic acid receptors; dermatology 1. Introduction Retinoids are defined as synthetic or natural derivatives of vitamin A that were first discovered in 1913. Retinol and retinyl ester are dietary forms of what is commonly known as vitamin A. These forms of vitamin A are not biologically active and require transformation, by cytosolic alcohol dehydrogenases (ADHs) and microsomal retinol dehydrogenases (MDHs), to become retinaldehyde, and subsequent oxidation by retinaldehyde dehydrogenases RALDH1, RALDH2, and RALDH3 to retinoic acid (RA) [1]. While the reverse transformation of retinaldehyde to retinol is possible through the DHRS3 enzyme Cells 2020, 9, 2660; doi:10.3390/cells9122660 www.mdpi.com/journal/cells CellsCells2020 2020, 9, ,9 2660, x FOR PEER REVIEW 22 of of 14 15 the DHRS3 enzyme activity, the retinaldehyde to RA conversion is irreversible [2]. RA exists in activity,several theisoforms retinaldehyde of which to the RA most conversion common is are irreversible all-trans [retinoic2]. RA existsacid and in several 9-cis retinoic isoforms acid of [2]. which All- thetrans-retinoic most common acid are (ATRA) all-trans is retinoicalso one acid of andthe main 9-cis retinoicphysiologically acid [2]. All-trans-retinoicactive metabolites acid of vitamin (ATRA) isA. alsoRetinoids, one of thewhich main are physiologically hydrophobic activecompounds, metabolites require of vitaminretinoid-binding A. Retinoids, proteins which for are stabilization hydrophobic in compounds,aqueous media. require Depending retinoid-binding on the localization, proteins for the stabilization stabilization in aqueousof retinoids media. is achieved Depending by binding on the localization,to different proteins the stabilization such as cellular of retinoids retinol-binding is achieved proteins by binding (CRBPs) to diff orerent cellular proteins retinoic such acid-binding as cellular retinol-bindingproteins (CRABPs), proteins the (CRBPs) interstitial or cellular retinol-bind retinoicing acid-binding protein (RBP proteins 3), and (CRABPs), plasma-retinol the interstitial binding retinol-bindingprotein (RBP 4) protein [3]. The (RBP half-life 3), and of plasma-retinol RA is around binding 1 h beca proteinuse (RBPit is rapidly 4) [3]. The metabolized half-life of by RA the is aroundcytochrome 1 h because P450 itenzymes is rapidly (CYP26s) metabolized [2]. byCYPs the cytochromeare involved P450 in enzymesATRA hydroxylation (CYP26s) [2]. CYPsand thus are involvedinactivation in ATRA of its hydroxylationfunction. RAs are and not thus only inactivation substrates of for its CYP26 function. enzymes RAs are but not are only also substrates potent CYP26 for CYP26inducers, enzymes therefore but creating are also potenta negativeCYP26 feedbackinducers, loop therefore [4]. creating a negative feedback loop [4]. ItIt is is believed believed that that ATRA ATRA deficiency, deficiency, mediated mediated by by CYPs CYPs or or other other mechanisms, mechanisms, is is associated associated with with cancercancer progression progression and and various various dermatological dermatological diseases diseases [5 [5].]. RetinoidsRetinoids are are usually usually classified classified in one in ofone the of three the generations;three generations; however, however, some researchers some researchers consider pyranonesconsider pyranones derivatives derivatives as the fourth as the generation. fourth gene Briefly,ration. naturally Briefly, occurring,naturally occurring, non-aromatic non-aromatic retinoids areretinoids classified are as classified the first generation,as the first generation, monoaromatic monoaromatic vitamin A derivatives vitamin A arederivatives the second are generation, the second whereasgeneration, retinoids whereas containing retinoids a cycliccontaining polyene a cyclic side-chain polyene are theside-chain third generation are the third [3]. Moregeneration detailed [3]. informationMore detailed about information retinoic acidabout and retinoic its signaling acid and pathways its signaling may pathways be found may in abe recent found reviewin a recent by Ghyselinckreview by Ghyselinck and Duester and (2019) Duester [2]. (2019) [2]. 2.2. Retinoic Retinoic Acid Acid Receptors Receptors and and Molecular Molecular Mechanism Mechanism of of Their Their Action Action RetinoicRetinoic acid acid receptors receptors are are key key developmental developmental regulators regulators and, and, as as such, such, function function as as a a molecular molecular switchswitch in in many many developmental developmental processes processes including including skin skin development. development. In the In absence the absence of a ligand, of a ligand, RARs repressRARs transcriptionrepress transcription through recruiting through histonerecruiting deacetylases histone deacetylases (HDAC) complexes (HDAC) such complexes as HDAC-N-CoR such as (negativeHDAC-N-CoR co-regulator) (negative or HDAC-SMRT co-regulator) (silencing or HDAC-SMRT mediator (silencing for retinoid mediator and thyroid for retinoid hormone and receptors) thyroid (Figurehormone1)[ 6receptors)]. (Figure 1) [6]. FigureFigure 1. 1.Mechanism Mechanism of of all-trans-retinoic all-trans-retinoic acid acid (ATRA) (ATRA) action. action. (A ()A In) In the the absence absence of aof ligand, a ligand, retinoid retinoid X (orX rexinoid)(or rexinoid) receptors receptors and retinoic and retinoic acid receptors acid receptor (RXR-RAR)s (RXR-RAR) heterodimers heterodimers bind to retinoic bind to acid retinoic response acid elementsresponse (RAREs) elements in the(RAREs) regulatory in the regions regulatory of target re genesgions andof target repress genes transcription and repress through transcription recruiting histonethrough deacetylases recruiting (HDAC)histone /deacetco-repressorylases (negative(HDAC)/co-repressor co-regulator (negative (N-CoR) orco-regulator silencing mediator (N-CoR) for or retinoidsilencing and mediator thyroid for hormone retinoid receptors and thyroid (SMRT)) hormone complexes. receptors HDACs (SMRT)) remove complexes. acetyl HDACs groups remove from nucleosomalacetyl groups histones from nucleosomal causing chromatin histones condensationcausing chromatin that precludes condensation binding that ofprecludes other factors binding and of ultimatelyother factors results and in ultimately the silencing results of gene in the expression. silencing ( Bof) Upongene expression. ligand binding, (B) Upon RAR undergoes ligand binding, structural RAR changeundergoes leading structural to dissociation change ofleading the co-repressor to dissociation complex of the and co-repressor association of complex co-activators and association