ATF-3 expression inhibits melanoma growth by downregulating ERK and AKT pathways

Abstract

Activating transcription factor 3 (ATF-3), a cyclic AMP-dependent transcription factor, has been shown to play a regulatory role in melanoma, although its function during tumor progression remains unclear. Here, we demonstrate that ATF-3 exhibits tumor suppressive function in melanoma. Specifically, ATF-3 nuclear expression was significantly diminished with melanoma progression from nevi to primary to metastatic patient melanomas, correlating low expression with poor prognosis. Significantly low expression of ATF-3 was also found in cultured human metastatic melanoma cell lines. Importantly, overexpression of ATF-3 in metastatic melanoma cell lines significantly inhibited cell growth, migration, and invasion in vitro; as well as abrogated tumor growth in a human melanoma xenograft mouse model in vivo. RNA sequencing analysis revealed downregulation of ERK and AKT pathways and upregulation in apoptotic-related genes in ATF-3 overexpressed melanoma cell lines, which was further validated by Western-blot analysis. In summary, this study demonstrated that diminished ATF-3 expression is associated with melanoma virulence and thus provides a potential target for novel therapies and prognostic biomarker applications.