Noxa upregulation by oncogenic activation of MEK/ERK through CREB promotes autophagy in human melanoma cells.

Yi Lun Liu,Qi Luan,Hsin-Yi Tseng,Lei Jin,Xu Guang Yan,Su Tang Guo,Richard A Scolyer,Fritz Lai,James S Wilmott,Chen Chen Jiang,Xiao Ying Liu,Xu Dong Zhang

doi:10.18632/oncotarget.2616

Abstract

Reduction in the expression of the anti-survival BH3-only proteins PUMA and Bim is associated with the pathogenesis of melanoma. However, we have found that the expression of the other BH3-only protein Noxa is commonly upregulated in melanoma cells, and that this is driven by oncogenic activation of MEK/ERK. Immunohistochemistry studies showed that Noxa was expressed at higher levels in melanomas than nevi. Moreover, the expression of Noxa was increased in metastatic compared to primary melanomas, and in thick primaries compared to thin primaries. Inhibition of oncogenic BRAFV600E or MEK downregulated Noxa, whereas activation of MEK/ERK caused its upregulation. In addition, introduction of BRAFV600E increased Noxa expression in melanocytes. Upregulation of Noxa was due to a transcriptional increase mediated by cAMP responsive element binding protein, activation of which was also increased by MEK/ERK signaling in melanoma cells. Significantly, Noxa appeared necessary for constitutive activation of autophagy, albeit at low levels, by MEK/ERK in melanoma cells. Furthermore, it was required for autophagy activation that delayed apoptosis in melanoma cells undergoing nutrient deprivation. These results reveal that oncogenic activation of MEK/ERK drives Noxa expression to promote autophagy, and suggest that Noxa has an indirect anti-apoptosis role in melanoma cells under nutrient starvation conditions.

Highlights

A characteristic of human melanoma is constitutive activation of the MEK/ERK signaling pathway [1, 2]
We report here that the increase in Noxa expression is driven by oncogenic activation of MEK/ ERK signaling through the transcription factor cAMP responsive element binding protein (CREB), and that Noxa contributes to constitutive activation of autophagy in melanoma cells
We present evidence that the BH3only protein Noxa is upregulated by oncogenic activation of MEK/ERK signaling, and that Noxa plays an important role in regulation of autophagy in melanoma cells

Summary

Introduction

A characteristic of human melanoma is constitutive activation of the MEK/ERK signaling pathway [1, 2]. Identification of oncogenic mutations of BRAF (with the most common mutation being a glutamic acid for valine substitution at position 600 (BRAFV600E)) as the primary driver of aberrant activation of the pathway in melanoma has led to development of mutant BRAF inhibitors in the treatment of the disease [1, 3,4,5]. These inhibitors have achieved unprecedented response rates in melanoma patients, the benefits are often of limited duration [1, 3,4,5]. The BH3only proteins PUMA and Bim are frequently reduced in melanomas, which is associated with poor survival of patients [12, 13]

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Conclusion