Author(s): Deni Firmansyah, Sulistiorini Indriaty, Sri Adi Sumiwi, Nyi Mekar Saptarini, Jutti Levita


DOI: 10.52711/0974-360X.2022.00472   

Address: Deni Firmansyah1,2*, Sulistiorini Indriaty3, Sri Adi Sumiwi1, Nyi Mekar Saptarini4, Jutti Levita1
1Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, West Java, Indonesia 45363.
2Department of Pharmacology, School of Pharmacy Muhammadiyah Cirebon, West Java, Indonesia 45153.
3Department of Technology of Pharmacy and Cosmetics, School of Pharmacy Muhammadiyah Cirebon, West Java, Indonesia 45153.
4Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, West Java, Indonesia 45363.
*Corresponding Author

Published In:   Volume - 15,      Issue - 6,     Year - 2022

It has been almost thirty years since the first publication on microphthalmia-associated transcription factor (MITF) in 1993. MITF, which plays an important role in the melanogenesis process, is an interesting target for melanoma therapy, due to its associates with melanoma survival. MITF promotes melanoma cell proliferation, whereas the sustained suppression of MITF expression causes aging. MITF contributes to differentiation, which involves breaking out of the cell cycle and triggering a melanogenesis, and this function appears to often persist during melanoma development given the frequently observed high pigmented lesions, even in the late stages of melanoma. Several drugs that could inhibit MITF e.g. histone deacetylase inhibitors, such as sodium butyrate and trichostatin A, have been proven could suppress M-MITF expression in melanoma cells. H1-receptor antagonists, particularly loratadine, could downregulate MITF and tyrosinase in melanocytes. Some plants can inhibit MITF e.g Gentiana veitchiorum Hemsl., Thymelaea hirsuta, Argania spinosa L. In this review, we update the information about MITF and describe the mechanism of its inhibitors in preventing melanogenesis.

Cite this article:
Deni Firmansyah, Sulistiorini Indriaty, Sri Adi Sumiwi, Nyi Mekar Saptarini, Jutti Levita. Microphthalmia Transcription Factor almost Thirty Years after: Its Role in Melanogenesis and its Plant-Derived Inhibitors. Research Journal of Pharmacy and Technology. 2022; 15(6):2825-0. doi: 10.52711/0974-360X.2022.00472

Deni Firmansyah, Sulistiorini Indriaty, Sri Adi Sumiwi, Nyi Mekar Saptarini, Jutti Levita. Microphthalmia Transcription Factor almost Thirty Years after: Its Role in Melanogenesis and its Plant-Derived Inhibitors. Research Journal of Pharmacy and Technology. 2022; 15(6):2825-0. doi: 10.52711/0974-360X.2022.00472   Available on:

1.    Ranga P. Management of Gingival Hyperpigmentation by Scalpel Technique. Research J. Pharm. and Tech. 2015; 8(2): Page 204-206. doi: 10.5958/0974-360X.2015.00037.2
2.    Bonaventure J, Domingues MJ, Larue L. Cellular and molecular mechanisms controlling the migration of melanocytes and melanoma cells. Pigment Cell Melanoma Res. 2013; 26(3):316–25. doi: 10.1111/pcmr.12080
3.    Chung YC, Kim MJ, Kang EY, Kim YB, Kim BS, Park SM, et al. Anti-melanogenic effects of hydroxyectoine via MITF inhibition by JNK, p38, and AKT pathways in B16F10 melanoma cells. Nat Prod Commun. 2019;14(6). doi: 10.1177%2F1934578X19858523
4.    Duraisamy A, Narayanaswamy N, K.P. Balakrishnan. Antioxidant and Anti-Tyrosinase Activity of Some Medicinal Plants. Research J. Pharmacognosy and Phytochemistry 2011; 3(2): 86-90.
5.    Saha D, Tamrakar A, Jana M, Mandal S. Skin Cancer: Dance of Death. Asian J. Pharm. Res. 2011; 1(2): Page 34-36
6.    Prapulla P. A Review on: Vitiligo- A Non-Contagious Chronic Disease different Types and Treatments. Asian J. Research Chem. 2019; 12(2): 120-125. doi: 10.5958/0974-4150.2019.00026.9
7.    Neeta, Dureja H. Reverse Phase High-Performance Liquid Chromatographic Estimation and In vitro Cytotoxicity of Boswellic Acids on A-375 Melanoma Cancer Cell lines. Asian J. Pharm. Ana. 2018; 8(1): 13-19. doi: 10.5958/2231-5675.2018.00003.0
8.    Sreelatha T, Subramanyam MV, Prasad MNG. A Survey work on Early Detection methods of Melanoma Skin Cancer. Research J. Pharm. and Tech. 2019; 12(5):2589-2596. doi: 10.5958/0974-360X.2019.00435.9
9.    Hartman ML, Czyz M. MITF in melanoma: Mechanisms behind its expression and activity. Cell Mol Life Sci. 2015;72(7):1249–60. doi: 10.1007/s00018-014-1791-0
10.    Haq R, Fisher DE. Biology and clinical relevance of the micropthalmia family of transcription factors in human cancer. J Clin Oncol. 2011;29(25):3474–82. doi: 10.1200/JCO.2010.32.6223
11.    Xie L, Zhang Y, Wu CL. Microphthalmia family of transcription factors associated renal cell carcinoma. Asian J Urol. 2019;6(4):312–20. doi: 10.1016/j.ajur.2019.04.003
12.    King R, Googe PB, Weilbaecher KN, Mihm MC Jr, Fisher DE. Microphthalmia Transcription Factor Expression in Cutaneous Benign, Malignant Melanocytic, and Nonmelanocytic Tumors. Am J Surg Pathol. 2001;25(1):51–7. doi: 10.1097/00000478-200101000-00005
13.    Wellbrock C, Arozarena I. Microphthalmia-associated transcription factor in melanoma development and MAP-kinase pathway targeted therapy. Pigment Cell Melanoma Res. 2015;28(4):390–406. doi: 10.1111/pcmr.12370
14.    Hartman ML, Czyz M. Pro-survival role of MITF in melanoma. J Invest Dermatol. 2015;135(2):352–8. doi: 10.1038/jid.2014.319
15.    Levy C, Khaled M, Fisher DE. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med. 2006;12(9):406–14. doi: 10.1016/j.molmed.2006.07.008
16.    Passeron T, Valencia JC, Bertolotto C, Hoashi T, Le Pape E, Takahashi K, et al. SOX9 is a key player in ultraviolet B-induced melanocyte differentiation and pigmentation. Proc Natl Acad Sci U S A. 2007;104(35):13984–9. doi: 10.1073/pnas.0705117104
17.    Strub T, Giuliano S, Ye T, Bonet C, Keime C, Kobi D, et al. Essential role of microphthalmia transcription factor for DNA replication, mitosis and genomic stability in melanoma. Oncogene. 2011;30(20):2319–32. doi: 10.1038/onc.2010.612
18.    D’Mello SAN, Finlay GJ, Baguley BC, Askarian-Amiri ME. Signaling pathways in melanogenesis. Int J Mol Sci. 2016;17(7):1–18. doi: 10.3390/ijms17071144
19.    Haq R, Shoag J, Andreu-perez P, Yokoyama S, Rowe GC, Frederick DT, et al. Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF. 2014;23(3):302–15. doi: 10.1016/j.ccr.2013.02.003
20.    Chen T, Zhao B, Liu Y, Wang R, Yang Y, Yang L, et al. MITF-M regulates melanogenesis in mouse melanocytes. J Dermatol Sci. 2018;90(3):253–62. doi: 10.1016/j.jdermsci.2018.02.008
21.    Karunakaran K, Malaiyappan JR, Muniyan RR. Protein-Protein Interaction of Mutated Agouti Signaling Protein (ASIP) to Melanocortin Receptor 1 (MC1R) in Melanoma Skin Cancer: An Insilico Study. Research J. Pharm. and Tech 2018; 11(9): 3913-3917. doi: 10.5958/0974-360X.2018.00718.7
22.    Möller K, Sigurbjornsdottir S, Arnthorsson AO, Pogenberg V, Dilshat R, Fock V, et al. MITF has a central role in regulating starvation-induced autophagy in melanoma. Sci Rep. 2019;9(1):1–12. doi: 10.1038/s41598-018-37522-6
23.    Hemesath TJ, Steingrímsson E, McGill G, Hansen MJ, Vaught J, Hodgkinson CA, et al. microphthalmia, A critical factor in melanocyte development, defines a discrete transcription factor family. Genes Dev. 1994;8(22):2770–80. doi: 10.1101/gad.8.22.2770
24.    Kuiper RP, Schepens M, Thijssen J, Schoenmakers EFPM, van Kessel AG. Regulation of the MiTF/TFE bHLH-LZ transcription factors through restricted spatial expression and alternative splicing of functional domains. Nucleic Acids Res. 2004;32(8):2315–22. doi: 10.1093/nar/gkh571
25.    Bharti K, Gasper M, Ou J, Brucato M, Clore-Gronenborn K, Pickel J, et al. A regulatory loop involving PAX6, MITF, and WNT signaling controls retinal pigment epithelium development. PLoS Genet. 2012;8(7):1–17. doi: 10.1371/journal.pgen.1002757
26.    Giuliano S, Cheli Y, Ohanna M, Bonet C, Beuret L, Bille K, et al. Microphthalmia-associated transcription factor controls the DNA damage response and a lineage-specific senescence program in melanomas. Cancer Res. 2010;70(9):3813–22.  doi: 10.1158/0008-5472.CAN-09-2913
27.    McGill GG, Haq R, Nishimura EK, Fisher DE. c-Met expression is regulated by Mitf in the melanocyte lineage. J Biol Chem. 2006;281(15):10365–73. doi: 10.1074/jbc.M513094200
28.    Wellbrock C, Rana S, Paterson H, Pickersgill H, Brummelkamp T, Marais R. Oncogenic BRAF regulates melanoma proliferation through the lineage specific factor MITF. PLoS One. 2008;3(7). doi: 10.1371/journal.pone.0002734
29.    Ojaswi G, Divya N, Digna P. Melanoma and its Drug Targets. Research J. Pharm. and Tech. 2016; 9(5): 562-570. doi: 10.5958/0974-360X.2016.00107.4
30.    Seberg HE, Van Otterloo E, Cornell RA. Beyond MITF: Multiple transcription factors directly regulate the cellular phenotype in melanocytes and melanoma. Pigment Cell Melanoma Res. 2017;30(5):454–66. doi: 10.1111/pcmr.12611
31.    Steingrímsson E, Tessarollo L, Pathak B, Hou L, Arnheiter H, Copeland NG, et al. Mitf and Tfe3, two members of the Mitf-Tfe family of bHLH-Zip transcription factors, have important but functionally redundant roles in osteoclast development. Proc Natl Acad Sci U S A. 2002;99(7):4477–82. doi: 10.1073/pnas.072071099
32.    De La Serna IL, Ohkawa Y, Higashi C, Dutta C, Osias J, Kommajosyula N, et al. The microphthalmia-associated transcription factor requires SWI/SNF enzymes to activate melanocyte-specific genes. J Biol Chem. 2006;281(29):20233–41. doi: 10.1074/jbc.M512052200
33.    Cheli Y, Ohanna M, Ballotti R, Bertolotto C. Fifteen-year quest for microphthalmia-associated transcription factor target genes. Pigment Cell Melanoma Res. 2010;23(1):27–40. doi: 10.1111/j.1755-148X.2009.00653.x
34.    Keenen B, Qi H, Saladi SV, Yeung M, de la Serna IL. Heterogeneous SWI/SNF Chromatin Remodeling Complexes Promote Expression of Microphthalmia —Associated Transcription Factor Target Genes in Melanoma. Physiol Behav. 2016;176(12):139–48. doi: 10.1038/onc.2009.304
35.    Carreira S, Goodall J, Aksan I, La Rocca SA, Galibert MD, Denat L, et al. Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression. Nature. 2005;433(7027):764–9. doi: 10.1038/nature03269
36.    Praetorius C, Grill C, Stacey SN, Metcalf AM, David U, Robinson KC, et al. A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway. 2014;155(5). doi: 10.1016/j.cell.2013.10.022
37.    Yasumoto K, Takeda K, Saito H, Watanabe K, Takahashi K, Shibahara S. Microphthalmia-associated transcription factor interacts with LEF-1, a mediator of Wnt signaling. EMBO J. 2002;21(11):2703–14. doi: 10.1093/emboj/21.11.2703. doi: 10.1093/emboj/21.11.2703
38.    Jiao Z, Mollaaghababa R, Pavan WJ, Antonellis A, Green ED, Hornyak TJ. Direct Interaction of Sox10 with the Promoter of Murine Dopachrome Tautomerase (Dct) and Synergistic Activation of Dct Expression with Mitf. Pigment Cell Res. 2004;17(4):352–62. doi: 10.1111/j.1600-0749.2004.00154.x
39.    Seberg HE, Van Otterloo E, Loftus SK, Liu H, Bonde G, Sompallae R, et al. TFAP2 paralogs regulate melanocyte differentiation in parallel with MITF. Vol. 13, PLoS Genetics. 2017. 1–32 p. doi: 10.1371/journal.pgen.1006636
40.    Yokoyama S, Feige E, Poling LL, Levy C, Widlund HR, Khaled M, et al. Pharmacologic suppression of MITF expression via HDAC inhibitors in the melanocyte lineage. Pigment Cell Melanoma Res. 2008;21(4):457–63. doi: 10.1111/j.1755-148X.2008.00480.x
41.    Moon HR, Jo SY, Kim HT, Lee WJ, Won CH, Lee MW, et al. Loratadine, an H 1 Antihistamine, Inhibits Melanogenesis in Human Melanocytes. Biomed Res Int. 2019;2019. doi: 10.1155/2019/5971546
42.    Nishio T, Usami M, Awaji M, Shinohara S, Sato K. Dual effects of acetylsalicylic acid on ERK signaling and Mitf transcription lead to inhibition of melanogenesis. Mol Cell Biochem. 2016;412:101–10. doi: 10.1007/s11010-015-2613-x
43.    Li H, DaSilva NA, Liu W, Xu J, Dombi GW, Dain JA, et al. Thymocid®, a Standardized Black Cumin (Nigella sativa) Seed Extract, Modulates Collagen Cross-Linking, Collagenase and Elastase Activities, and Melanogenesis in Murine B16F10 Melanoma Cells.Nutrients. 2020; 12(7):1–16. doi: 10.3390/nu12072146
44.    Sato K, Takei M, Iyota R, Muraoka Y, Nagashima M, Yoshimura Y. Indomethacin inhibits melanogenesis via down-regulation of Mitf mRNA transcription. Biosci Biotechnol Biochem. 2017;81(12):2307–13. doi: 10.1080/09168451.2017.1394812
45.    Shaikh G, Deshmukh G. A Review on Anti-ageing and Whitening effect. Research J. Pharm. and Tech. 2019; 12(10):5059-5066. doi: 10.5958/0974-360X.2019.00878.3
46.    Lehraiki A, Abbe P, Cerezo M, Rouaud F, Regazzetti C, Chignon-Sicard B, et al. Inhibition of melanogenesis by the antidiabetic metformin. J Invest Dermatol. 2014;134(10):2589–97. doi: 10.1038/jid.2014.202
47.    Wu QY, Wong ZCF, Wang C, Fung AHY, Wong EOY, Chan GKL, et al. Isoorientin derived from Gentiana veitchiorum Hemsl. flowers inhibits melanogenesis by down-regulating MITF-induced tyrosinase expression. Phytomedicine. 2019;57:129–36. doi: 10.1016/j.phymed.2018.12.006
48.    Villareal MO, Han J, Yamada P, Shigemori H, Isoda H. Hirseins inhibit melanogenesis by regulating the gene expressions of Mitf and melanogenesis enzymes. Exp Dermatol. 2010;19(5):450–7. doi: 10.1111/j.1600-0625.2009.00964.x
49.    Villareal MO, Kume S, Bourhim T, Bakhtaoui FZ, Kashiwagi K, Han J, et al. Activation of MITF by argan oil leads to the inhibition of the tyrosinase and dopachrome tautomerase expressions in B16 murine melanoma cells. Evidence-based Complement Altern Med. 2013;2013. doi: 10.1155/2013/340107
50.    Tsao YT, Kuo CY, Kuan YD, Lin HC, Wu LH, Lee CH. The extracts of astragalus membranaceus inhibit melanogenesis through the ERK signaling pathway. Int J Med Sci. 2017;14(11):1049–53. doi: 10.7150/ijms.20335
51.    Alam MB, Ahmed A, Motin MA, Kim S, Lee SH. Attenuation of melanogenesis by Nymphaea nouchali (Burm. f) flower extract through the regulation of cAMP/CREB/MAPKs/MITF and proteasomal degradation of tyrosinase. Sci Rep. 2018;8(1):1–14. doi: 10.1038/s41598-018-32303-7
52.    Zhao P, Alam MB, An H, Choi HJ, Cha YH, Yoo CY, et al. Antimelanogenic effect of an oroxylum indicum seed extract by suppression of mitf expression through activation of mapk signaling protein. Int J Mol Sci. 2018;19(3). doi: 10.3390/ijms19030760
53.    Lee R, Ko HJ, Kim K, Sohn Y, Min SY, Kim JA, et al. Anti-melanogenic effects of extracellular vesicles derived from plant leaves and stems in mouse melanoma cells and human healthy skin. J Extracell Vesicles. 2020;9(1):1-11. doi: 10.1080/20013078.2019.1703480
54.    Choi MH, Jo HG, Yang JH, Ki SH, Shin HJ. Antioxidative and anti-melanogenic activities of bamboo stems (Phyllostachys nigra variety henosis) via PKA/CREB-mediated MITF downregulation in B16F10 melanoma cells. Int J Mol Sci. 2018;19(2):1–18. doi: 10.3390/ijms19020409
55.    Liu ZJ, Wang YL, Li QL, Yang L. Improved antimelanogenesis and antioxidant effects of polysaccharide from cuscuta Chinensis lam seeds after enzymatic hydrolysis. Brazilian J Med Biol Res. 2018;51(7):1–8. doi: 10.1590/1414-431x20187256
56.    Kaneda T, Matsumoto M, Sotozono Y, Fukami S, Eko A. Cycloartane triterpenoid (23 R, 24 E)‑ 23 ‑ acetoxymangiferonic acid inhibited proliferation and migration in B16 ‑ F10 melanoma via MITF downregulation caused by inhibition of both β ‑ catenin and c ‑ Raf – MEK1 – ERK signaling axis. 2020;1(2019):47–58. doi: 10.1007/s11418-018-1233-7
57.    Antony J, Saikia M, Vinod V, Nath LR, Katiki MR, Murty MSR, et al. DW-F5: A novel formulation against malignant melanoma from Wrightia tinctoria. Sci Rep. 2015;5(June):1-14. doi: 10.1038/srep11107
58.    Koo JH, Hyoung TK, Yoon HY, Kwon KB, Choi IW, Sung HJ, et al. Effect of xanthohumol on melanogenesis in B16 melanoma cells. Exp Mol Med. 2008;40(3):313–9. doi: 10.3858/emm.2008.40.3.313
59.    Kim JW, Kim H Il, Kim JH, Kwon OC, Son ES, Lee CS, et al. Effects of ganodermanondiol, a new melanogenesis inhibitor from the medicinal mushroom Ganoderma lucidum. Int J Mol Sci. 2016;17(11):1–12. doi: 10.3390/ijms17111798
60.    Kumar KJS, Vani MG, Wu PC, Lee HJ, Tseng YH, Wang SY. Essential oils of Alpinia nantoensis retard forskolin-induced melanogenesis via erk1/2-mediated proteasomal degradation of mitf. Plants. 2020;9(12):1–17. doi: 10.3390/plants9121672
61.    Shin SH, Lee YM. Glyceollins, a novel class of soybean phytoalexins, inhibit SCF-induced melanogenesis through attenuation of SCF/c-kit downstream signaling pathways. Exp Mol Med. 2013;45(2):e17-9. doi: 10.1038/emm.2013.20
62.    Li HX, Park JU, Su XD, Kim KT, Kang JS, Kim YR, et al. Identification of anti-melanogenesis constituents from morus alba L. Leaves. Molecules. 2018;23(10):1–11. doi: 10.3390/molecules23102559
63.    Lee DY, Jeong YT, Jeong SC, Lee MK, Min JW, Lee JW, et al. Melanin biosynthesis inhibition effects of ginsenoside Rb2 isolated from panax ginseng berry. J Microbiol Biotechnol. 2015;25(12):2011–5. doi: 10.4014/jmb.1505.05069
64.    Wang JY, Chen H, Wang YY, Wang XQ, Chen HY, Zhang M, et al. Network pharmacological mechanisms of Vernonia anthelmintica (L.) in the treatment of vitiligo: Isorhamnetin induction of melanogenesis via up-regulation of melanin-biosynthetic genes. BMC Syst Biol. 2017;11(1):1–12. doi: 10.1186/s12918-017-0486-1
65.    Ko HH, Tsai YT, Yen MH, Lin CC, Liang CJ, Yang TH, et al. Norartocarpetin from a folk medicine Artocarpus communis plays a melanogenesis inhibitor without cytotoxicity in B16F10 cell and skin irritation in mice. BMC Complement Altern Med. 2013;13:1–12. doi: 10.1186/1472-6882-13-348
66.    Kollipara RK, Tallapaneni V, Sanapalli BKR, Kumar VG, Karri VVSR. Curcumin Loaded Ethosomal Vesicular Drug Delivery System for the Treatment of Melanoma Skin Cancer. Research J. Pharm. and Tech.  2019; 12(4): 1783-1792. doi: 10.5958/0974-360X.2019.00298.1

Recomonded Articles:

Research Journal of Pharmacy and Technology (RJPT) is an international, peer-reviewed, multidisciplinary journal.... Read more >>>

RNI: CHHENG00387/33/1/2008-TC                     
DOI: 10.5958/0974-360X 

56th percentile
Powered by  Scopus

SCImago Journal & Country Rank

Recent Articles


Not Available