Guanine Deaminase in Human Epidermal Keratinocytes Contributes to Skin Pigmentation

Abstract

Epidermal keratinocytes are considered as the most important neighboring cells that modify melanogenesis. Our previous study used microarray to show that guanine deaminase (GDA) gene expression is highly increased in melasma lesions. Hence, we investigated the role of GDA in skin pigmentation. We examined GDA expression in post-inflammatory hyperpigmentation (PIH) lesions, diagnosed as Riehl’s melanosis. We further investigated the possible role of keratinocyte-derived GDA in melanogenesis by quantitative PCR, immunofluorescence staining, small interfering RNA-based GDA knockdown, and adenovirus-mediated GDA overexpression. We found higher GDA positivity in the hyperpigmentary lesional epidermis than in the perilesional epidermis. Both UVB irradiation and stem cell factor (SCF) plus endothelin-1 (ET-1) were used, which are well-known melanogenic stimuli upregulating GDA expression in both keratinocyte culture alone and keratinocyte and melanocyte coculture. GDA knockdown downregulated melanin content, while GDA overexpression promoted melanogenesis in the coculture. When melanocytes were treated with UVB-exposed keratinocyte-conditioned media, the melanin content was increased. Also, GDA knockdown lowered SCF and ET-1 expression levels in keratinocytes. GDA in epidermal keratinocytes may promote melanogenesis by upregulating SCF and ET-1, suggesting its role in skin hyperpigmentary disorders.

Upregulated Guanine Deaminase Is Involved in Hyperpigmentation of Seborrheic Keratosis via Uric Acid Release

“…There was no enhancement of melanogenesis from melanocytes by recombinant GDA either (Figure 1d), suggesting roles of melanogenic factors other than GDA released from GDA-overexpressing keratinocytes in melanogenesis. An interaction between melanogenic growth factors and GDA in keratinocytes has been mentioned [28]. We also found that levels of melanogenic growth factors such as basic fibroblast growth factor and SCF were increased in keratinocytes by GDA over expression (Supplementary Figure S1).…”

“…Increased levels of tyrosinase and MITF by coculturing with GDAoverexpressing keratinocytes (Figure 1a) suggested a role of GDA in enhancing melanogenesis. In fact, GDA upregulation has been reported in melasma [26][27][28], a representative pigmentary skin disorder, in addition to seborrheic keratosis [5]. We have also detected upregulation of GDA in melasma (data not shown).…”

Inhibition of melanogenesis by Aster yomena callus pellet extract in melanoma cells and patients with skin pigmentation

“…Although melanin plays a positive role in protecting the skin, excessive melanin synthesis due to severe stimuli, such as UV rays may lead to pigmentation, such as freckles, and skin spots, and the toxicity of melanin precursors may lead to cell death and skin cancer 28 , 29 . In fact, keratinocyte-derived mediators, such as α-MSH, basic fibroblastic growth factor, stem cell factor, endothelin-1, produced by UV stimulation can result in the activation of melanocytes, consequently promoting melanogenesis 30 , 31 . Interestingly, we recently observed that AYC-P-E exerts anti-photoaging functions in UVB-irradiated human keratinocytes by improving cell viability, inhibiting elastase, forming Type I procollagen, and inhibiting TNF-α.…”

“…To investigate the cytotoxic effect of AYC-P-E in melanoma cells, B16F10 cells were seeded in a 6-well plate at a density of 1×10 5 cells/well for 12 h, and the media were removed. Then, culture medium containing AYC-P-E at various concentrations (15,30,60, and 120 μl/ml) was added. After 72 h, cells were harvested and washed twice with phosphate-buffered saline (PBS).…”

Unfolding New Roles for Guanine-Based Purines and Their Metabolizing Enzymes in Cancer and Aging Disorders

“…ROS, in turn, can react with GUA and generate 8-oxo-7,8-dihydroguanine (8-oxoG) which is known to induce DNA damage and skin senescence (Valavanidis et al, 2009). Of note, GDA has also a direct role in skin lesions by interacting with several cytokines and growth factors, thus promoting melanogenesis (Jung et al, 2020).…”