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in mammalian regulation, it is high- See related article on pg 784 ly likely that SNPs that alter the regula- tion of gene expression may function at some distance from the target gene. This NADPH:Quinone Oxidoreductase-1 concept is exemplified in the context of biology by recent associa- as a New Regulatory Enzyme That tion studies into pigmentation regulation in the eye. The presence of a single SNP Increases Synthesis located within intron 86 of the HERC2 Yuji Yamaguchi1, Vincent J. Hearing2, Akira Maeda1 gene was found to be the major determi- 1 nant of blue/brown eye-color phenotypes and Akimichi Morita in (Sturm et al., 2008). Although Most hypopigmenting reagents target the inhibition of , the key this finding may have provided impe- enzyme involved in melanin synthesis. In this issue, Choi et al. report that tus to investigate the role of this gene in NADPH:quinone oxidoreductase-1 (NQO1) increases melanin synthesis, melanocyte function, prior knowledge probably via the suppression of tyrosinase degradation. Because NQO1 of melanocyte biology suggests that this was identified by comparing normally pigmented with SNP is likely to regulate the expression hypopigmented acral lentiginous melanoma cells, these results suggest of the neighboring OCA2 gene, with its various hypotheses regarding the carcinogenic origin of the latter. role already firmly established in the pro- Journal of Investigative Dermatology (2010) 130, 645–647. doi:10.1038/jid.2009.378 cess of pigmentation. To fully appreciate and extend these findings, the genetic associations and locus interactions of these candidate sus- Enzymes that regulate skin pigmentation plays the critical role in melanin syn- ceptibility must also be examined Melanin synthesis by melanocytes is one thesis, and various factors, including in the wider context of the autoimmune of the most important parameters regu- the copper-transporter ATP7A, have diseases that accompany . lating skin pigmentation (Yamaguchi et the capacity to modulate its enzymat- al., 2007a), and more than 150 pigment ic activity (Setty et al., 2008). Indeed, CONFLICT OF INTEREST The authors state no conflict of interest. genes have now been identified. The most hypopigmenting reagents are cosmetic industry has developed numer- intended to suppress tyrosinase activ- References ous hypopigmenting (depigmenting or ity. Additionally, two variants of oculo­ Boissy RE, Spritz RA (2009) Frontiers and whitening) reagents to suppress melanin cutaneous in humans (OCA1A controversies in the pathobiology of vitiligo: synthesis in order to meet the needs of and OCA1B) are caused by in separating the wheat from the chaff. Exp Dermatol 18:583–5 customers with hyperpigmenting condi- tyrosinase. Tyrosinase is the rate-limiting tions such as chloasma () and/ enzyme that mediates hydroxylation Jin Y, Mailloux CM, Gowan K et al. (2007) NALP1 in vitiligo-associated multiple autoimmune or ephelides () (Solano et al., of tyrosine to dopaqui­none and the disease. N Engl J Med 356:1216–25 2006). There is also a demand for hyper- oxidation of 5,6-dihydroxyindole (DHI) Jin Y, Riccardi SL, Gowan K et al. (2010) Fine- pigmenting (artificial tanning) reagents to indole-5,6-quinone, which pro- mapping of vitiligo susceptibility loci on to treat vitiligo and other hypopigment- duces eumelanin (Figure 1). DCT is a 7 and 9 and interactions with NLRP1 (NALP1). J Invest Dermatol 130:774–83 ing diseases, and there are societies in tautomerase that converts dopachrome which tanning is perceived as beautiful to DHI-2-carboxylic acid (DHICA), Liu L, Li C, Gao J et al. (2009) Genetic polymorphisms of glutathione S-transferase and and healthy. Taking together these obser- whereas TYRP1 is a DHICA oxidase that risk of vitiligo in the Chinese population. J Invest vations, methods of controlling melanin further stimulates eumelanin synthesis. Dermatol 129:2646–52 synthesis have considerable significance Consequently, melanogenic enzymes Spritz RA, Gowan K, Bennett DC et al. for patients with pigmentary disorders that act within are critical (2004) Novel vitiligo susceptibility loci and in the general marketplace. for the production of the pigmented bio- on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on 17, Enzymes involved in melanin synthe- polymer melanin. and their roles in an autoimmune diathesis. sis include tyrosinase, tyrosinase-related Am J Hum Genet 74:188–91 protein-1 (TYRP1), and dopachrome NQO1 as an enhancer Sturm RA, Duffy DL, Zhao ZZ et al. (2008) A single tautomerase (DCT) (Yamaguchi and of tyrosinase activity SNP in an evolutionary conserved region Hearing, 2009). Among these enzymes Yoon’s group has identified NADPH: within intron 86 of the HERC2 gene determines blue-brown eye color. Am J Hum Genet in the tyrosinase family, tyrosinase quinone oxidoreductase-1 (NQO1) 82:424–31 Taieb A, Picardo M (2009) Clinical practice. Vitiligo. N Engl J Med 360:160–9 1Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of 2 Waterman EA, Gawkrodger DJ, Watson PF et al. Medical Sciences, Nagoya, Japan and Laboratory of Cell Biology, National Cancer Institute, (2009) Autoantigens in vitiligo identified by National Institutes of Health, Bethesda, Maryland, USA the serological selection of a phage-displayed Correspondence: Yuji Yamaguchi, Department of Geriatric and Environmental Dermatology, Nagoya melanocyte cDNA expression library. J Invest City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya Dermatol 130:230–40 467-8601, Japan. E-mail: [email protected]

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(Dinkova-Kostova et al., 2002). Keap1 Clinical Implications binds to Nrf2, which translocates to • NQO1 is a newly identified regulatory enzyme that increases tyrosinase the nucleus in response to carcinogens activity, probably by suppressing its degradation. and oxidants, followed by activation • Identification of a novel regulatory enzyme provides new of the antioxidant response element pharmacologic opportunities to treat pigmentary disorders. of the NQO1 gene. It seems likely that upregulated NQO1 enhances the • Likewise, identification of a novel enzyme may provide leads for the expression of tyrosinase independent- pharmacologic treatment of melanoma. ly of its regulation by MITF, because NQO1 does not affect the expression of tyrosinase at the mRNA level or the expression of MITF at either the by comparing hypopigmented acral mRNA level in tissue culture. Choi mRNA or the protein levels. Choi et lentiginous melanoma cells with et al. conclude that NQO1 positively al. hypothesize that NQO1 suppresses their normal counterparts, pigmented regulates melanin synthesis, probably the ubiquitin–proteasome system that melanocytes obtained from the back by stabilizing tyrosinase protein. would normally degrade tyrosinase. skin of the same patient (Choi et al., These findings triggered the Other factors that affect tyrosinase this issue). NQO1 is an enzyme that authors’ interest in elucidating the trafficking in melanocytes may be catalyzes the two-electron reduction mechanism(s) by which NQO1 involved in the selective upregulation and the detoxification of quinones upregulates tyrosinase activity. of tyrosinase in response to NQO1. (including coenzyme Q10, also known Keap1 (Kelch-like ECH-associated as ubiquinone, and p-benzoquinone) protein 1) regulates the expression NQO1 as a therapeutic target to broad-sense hydroquinones of NQO1 via Nrf2, a member of the for acral melanoma (including ubiquinol and narrowly NF-E2 family of nuclear basic leucine To identify NQO1 as an enzyme that defined hydroquinone, also known as zipper transcription factors (Figure 2) increases melanin synthesis, Choi 1,4-benzenediol). The lower section of Figure 1 shows a representative reac- tion for NQO1, which may play a role Eumelanin in melanin synthesis, specifically the conversion of dopaquinone to dopa­ Tyrosinase TYRP1 chrome via leuko­dopachrome. NQO1, CO H HO HO one of the phase 2 enzymes, ordinar- 2 NH 2 HO HO CO H ily protects cells against free radical HO N N 2 damage and oxidative stress. Because H H Tyrosine hydro­quinone is a well-known hypop- DHI DHICA CO igmenting reagent, NQO1 may nega- Tyrosinase 2 DCT tively regulate skin pigmentation via an HO increased production of hydroquinone O CO2H O

NH2 within melanocytes. Indeed, the authors HO CO H CO2H O N 2 HO N demonstrate that overexpression of H NQO1 results in a modest decrease in Dopaquinone Leukodopachrome Dopachrome TYRP1 and microphthalmia-associated Cysteine transcription factor (MITF, the mas- ter regulator of skin pigmentation) at NADPH NADP+ Pheomelanin protein levels (Figure 2). O OH On the other hand, melanogenesis increased in concert with increasing NQO1 levels of NQO1 in the various mela- O OH noma cell lines tested. Additionally, p-Benzoquinone Hydroquinone the inhibition of NQO1 resulted in a decrease in MITF, tyrosinase, and Figure 1. Key players in melanin biosynthesis and NQO1 as an oxidoreductase that mediates TYRP1 (but not DCT) at protein lev- the conversion of quinones to hydroquinones. Tyrosinase, DCT, and TYRP1 are enzymes that els in tissue culture and in a reduc- convert tyrosine (and DHI) to dopaquinone (and eumelanin), dopachrome to DHICA, and DHICA to tion in melanin pigment using a eumelanin, respectively. Pheomelanin derives from dopaquinone based on the presence of cysteine. NQO1 is an oxidoreductase that mediates the conversion of quinones (including p-benzoquinone and zebrafish model. Finally, overex- coenzyme Q10) to hydroquinones (including narrowly defined hydroquinone and ubiquinol). DCT, pression of NQO1 resulted in an dopachrome tautomerase; DHI, 5,6-dihydroxyindole; DHICA, 5,6-dihydroxyindole-2-carboxylic acid; increase in tyrosinase protein and in NADPH, nicotinamide adenine dinuclueotide phosphate; NQO1, NADPH:quinone oxidoreductase-1; its enzymatic activity, but not at the TYRP1, tyrosinase-related protein-1. Adapted from PubChem (http://pubchem.ncbi.nlm.nih.gov).

646 Journal of Investigative Dermatology (2010), Volume 130 commentary

important for studying carcinogenesis and metastasis by AM cells. Melanocyte Concluding remarks In summary, Choi et al. (2010) have Melanin identified NQO1 as a new pigmenta- synthesis tion regulatory enzyme that increases tyrosinase activity, probably by sup- pressing its degradation. Future stud- Keap1 Nrf2 Tyrosinase ies should elucidate the mechanism(s) by which AM occurs via NQO1 and/ Keap1 Nrf2 MITF TYRP1 or other factors identified in their ? ? microarray analyses at the gene level ARE and in their proteomics analyses at the protein level. NQO1 DCT

CONFLICT OF INTEREST The authors state no conflict of interest.

Figure 2. Scheme summarizing how NQO1 regulates melanin synthesis in melanocytes. NQO1 References is regulated by ARE, which is enhanced by Nrf2. Nrf2 migrates into the nucleus from the cytoplasm, Choi T-Y, Sohn K-C, Kim J-H et al. (2010) Impact where it is released from Keap1 in response to various stimuli. NQO1 does not significantly of NAD(P)H:quinone oxidoreductase-1 on affect the expression of MITF, TYRP1, or DCT, but it increases the catalytic activity and protein pigmentation. J Invest Dermatol 130:784–92 level of tyrosinase and thereby induces melanin synthesis. Vertical blue arrows indicate up- or Curtin JA, Fridlyand J, Kageshita T et al. (2005) downregulation in response to NQO1 stimulation; horizontal blue arrow indicates that NQO1 Distinct sets of genetic alterations in melanoma. stimulation has no effect on DCT expression. Blue labels indicate data presented by Choi et al. N Engl J Med 353:2135–47 (2010). ARE, antioxidant response element; DCT, dopachrome tautomerase; Keap1, Kelch-like ECH- Dinkova-Kostova AT, Holtzclaw WD, Cole RN et al. associated protein-1; MITF, microphthalmia-associated transcription factor; NQO1, NADPH:quinone (2002) Direct evidence that sulfhydryl groups oxidoreductase-1; Nrf2, an NF-E2 family of nuclear basic leucine zipper transcription factors; TYRP1, of Keap1 are the sensors regulating induction tyrosinase-related protein-1. of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci USA 99:11908–13 Murata H, Ashida A, Takata M et al. (2007) et al. used two established and high- and N-RAS mutations are observed Establishment of a novel melanoma cell ly sensitive analytical approaches— in melanomas with chronic sun- line SMYM-PRGP showing cytogenetic and biological characteristics of the radial microarrays at the gene level and induced damage, but they are rare growth phase of acral melanomas. Cancer Sci proteomics at the protein level—and in melanomas without chronic sun- 98:958–63 they compared less pigmented cells induced damage, in mucosal mela- Namiki T, Yanagawa S, Izumo T et al. (2005) with normally pigmented cells. nomas, and in AMs (Curtin et al., Genomic alterations in primary cutaneous In addition to their findings con- 2005). Even normal melanocytes are melanomas detected by metaphase comparative genomic hybridization with laser capture or cerning the regulation of skin pig- able to adopt different phenotypes in manual microdissection: 6p gains may predict mentation, the investigators elegantly response to external stimuli such as poor outcome. Cancer Genet Cytogenet established an acral melanoma (AM) dickkopf 1, an inhibitor of the Wnt/β- 157:1–11 cell line, which has been reported only catenin signaling pathway (Yamaguchi Setty SR, Tenza D, Sviderskaya EV et al. (2008) rarely (Murata et al., 2007). Because et al., 2007b). In that sense, the ideal Cell-specific ATP7A transport sustains copper- dependent tyrosinase activity in melanosomes. AM has a unique phenotype, in that comparisons would have been among Nature 454:1142–6 amplifications of narrow regions of primary AM cells, metastatic AM Solano F, Briganti S, Picardo M et al. (2006) the genome (gains of chromosomes cells, and normal melanocytes locat- Hypopigmenting agents: an updated review 6p or 1q) are often observed in AM ed between the two sites (primary on biological, chemical and clinical aspects. patients as compared with non-AM and metastatic AM sites). However, Pigment Cell Res 19:550–71 patients (Namiki et al., 2005), com- Choi et al. identified NQO1 as an AM Yamaguchi Y, Brenner M, Hearing VJ (2007a) The regulation of skin pigmentation. J Biol Chem parison with normal melanocytes may carcinogenic candidate; to explain 282:27557–61 elucidate the mechanism(s) by which the mechanism, they suggested that Yamaguchi Y, Passeron T, Watabe H et al. AM transformation occurs. Skin is het- the loss of NQO1 in AM cells facili- (2007b) The effects of dickkopf 1 on gene erogeneous (site-specifically different) tates carcinogenesis due to the loss expression and Wnt signaling by melanocytes: in terms of the presence or absence of its suppressive scavenger effect in mechanisms underlying its suppression of melanocyte function and proliferation. of hair, degree of pigmentation, and the face of oxidative stress caused by J Invest Dermatol 127:1217–25 epidermal thickness. Melanoma types reactive oxygen species. Other factors Yamaguchi Y, Hearing VJ (2009) Physiological obtained from various body sites shown in Supplementary Tables 1 factors that regulate skin pigmentation. reflect different characteristics; BRAF and 2 of their article are potentially Biofactors 35:193–9

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