ITAC induces the melanocytic migration and hypopigmentation through destabilizing p53 via HDAC5: A possible role of ITAC in pigment-related disorders

Summary

Background

Cell migration plays a major role in the immune response and in tumorigenesis. Interferon-inducible T-cell alpha chemoattractant (ITAC) elicits a strong chemotactic response from immune cells.

Objectives

To examine the effect of ITAC on the melanocytic migration and pigmentation and its involvement in the related disorders, and to investigate potential key players in these processes.

Methods

Human melanocytes or melanoma cells were treated with ITAC and migration assay was performed. Global gene expression analysis was performed to find genes regulated by ITAC treatment. The function of key players involved in ITAC-induced cellular processes was addressed using knockdown or overexpression experiments in combination with ITAC treatment. ITAC expression in an inflammation-associated hypopigmentary disorder, vitiligo, were examined.

Results

Among CXCR3 ligands, only ITAC induces melanocyte migration. ITAC treatment up-regulated the expression of histone deacetylase 5 (HDAC5) and down-regulated that of p53, a known target of HDAC5. Through knockdown or overexpression of HDAC5 and p53, we confirmed that HDAC5 mediates ITAC-induced migration by decreasing the levels of p53 via deacetylation. In addition, ITAC treatment could decrease pigmentation in a p53- and HDAC5-dependent manner. Finally, the increased migration of human melanoma cells by ITAC treatment and the increased ITAC expression in the epidermis of vitiligo skins were verified.

Conclusions

This study provides in vitro evidences for the migratory and hypopigmentation effects of ITAC on melanocytic cells and translational insights on the roles of ITAC in pathological conditions, and suggests that HDAC5 and its substrate p53 are potent targets for regulating ITAC-induced cellular processes.

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