Inhibition of NAT10 Suppresses Melanogenesis and Melanoma Growth by Attenuating Microphthalmia-Associated Transcription Factor (MITF) Expression.

Taek-In Oh,Yoon-Mi Lee,Beong-Ou Lim,Ji-Hong Lim

doi:10.3390/ijms18091924

Abstract

N-acetyltransferase 10 (NAT10) has been considered a target for the treatment of human diseases such as cancer and laminopathies; however, its functional role in the biology of melanocytes is questionable. Using a small molecule or small interfering RNA targeting NAT10, we examined the effect of NAT10 inhibition on melanogenesis and melanoma growth in human and mouse melanoma cells. Genetic silencing or chemical inhibition of NAT10 resulted in diminished melanin synthesis through the suppression of melanogenesis-stimulating genes such as those encoding dopachrome tautomerase (DCT) and tyrosinase in B16F10 melanoma cells. In addition, NAT10 inhibition significantly increased cell cycle arrest in S-phase, thereby suppressing the growth and proliferation of malignant melanoma cells in vitro and in vivo. These results demonstrate the potential role of NAT10 in melanogenesis and melanoma growth through the regulation of microphthalmia-associated transcription factor (MITF) expression and provide a promising strategy for the treatment of various skin diseases (melanoma) and pigmentation disorders (chloasma and freckles).

Highlights

N-acetyltransferase 10 (NAT10), a member of GCN5-related N-acetyltransferases (GNAT), has been reported to be involved in the regulation of ribosome biogenesis, histone acetylation, DNA damage response, microtubule reorganization, and cell cycle progression [1,2,3,4]
NAT10 may be involved in the biology of melanocyte, a cell subtype responsible for preventing skin disorder caused by ultraviolet (UV)-induced DNA damage
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Summary

Introduction

N-acetyltransferase 10 (NAT10), a member of GCN5-related N-acetyltransferases (GNAT), has been reported to be involved in the regulation of ribosome biogenesis, histone acetylation, DNA damage response, microtubule reorganization, and cell cycle progression [1,2,3,4]. The expression of NAT10 is reported to increase in response to DNA damage, and ectopic expression of NAT10 maintains cell survival upon DNA damage stress [5]. NAT10 may be involved in the biology of melanocyte, a cell subtype responsible for preventing skin disorder caused by ultraviolet (UV)-induced DNA damage. A recent study demonstrated that a small molecule, “remodelin”, targeting NAT10 restores nuclear shape of Hutchinson–Gilford progeria syndrome (HGPS)-derived patient cells via microtubule reorganization [1]

Results

Discussion

Conclusion