Cytoplasmic accumulation of NCoR in malignant melanoma: consequences of altered gene repression and prognostic significance.

Fernando Gallardo,Lluís Espinosa,Beatriz Bellosillo,Ricard Garcia-Carbonell,Montserrat Arumí-Uria,Joan Bertran,Abel González-Perez,Nuria Lopez-Bigas,Ramon Maria Pujol,Sonia Segura,Anna Bigas,Andreina Padrón,Cristina Rius,Lara Nonell,Mar Iglesias

doi:10.18632/oncotarget.3252

Fernando Gallardo, Lluís Espinosa + Show 13 more

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https://doi.org/10.18632/oncotarget.3252

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Abstract

Invasive malignant melanoma (MM) is an aggressive tumor with no curative therapy available in advanced stages. Nuclear corepressor (NCoR) is an essential regulator of gene transcription, and its function has been found deregulated in different types of cancer. In colorectal cancer cells, loss of nuclear NCoR is induced by Inhibitor of kappa B kinase (IKK) through the phosphorylation of specific serine residues. We here investigate whether NCoR function impacts in MM, which might have important diagnostic and prognostic significance. By IHC, we here determined the subcellular distribution of NCoR in a cohort of 63 primary invasive MM samples, and analyzed its possible correlation with specific clinical parameters. We therefore used a microarray-based strategy to determine global gene expression differences in samples with similar tumor stage, which differ in the presence of cytoplasmic or nuclear NCoR. We found that loss of nuclear NCoR results in upregulation of a specific cancer-related genetic signature, and is significantly associated with MM progression. Inhibition of IKK activity in melanoma cells reverts NCoR nuclear distribution and specific NCoR-regulated gene transcription. Analysis of public database demonstrated that inactivating NCoR mutations are highly prevalent in MM, showing features of driver oncogene.

Highlights

Malignant melanoma (MM) is the most aggressive form of skin cancer accounting for most skin cancer deaths
We found an inverse correlation (–0.628) between the percentages of nuclear NCoR (nNCoR) and the Breslow index (p < 0.001), with samples showing lower percentage of nNCoR positive cells corresponding to the greater Breslow index (Figure 1B, Table 1)
The analysis demonstrated a significant association between loss of nNCoR localization and higher mitotic index (p < 0.01) and a statistical trend with ulceration (p = 0.051)

Summary

Introduction

Malignant melanoma (MM) is the most aggressive form of skin cancer accounting for most skin cancer deaths. The RAS/RAF/MEK/ERK pathway is a crucial regulator of proliferation and cell survival in different physiologic and pathologic systems, and it is supposed to contribute to tumor progression in part through the activation of other downstream pathways such as NF-κB [2]. The NF-κB transcription factor is a homo- or heterodimeric factor involving five different proteins (p50, p52, p65, c-Rel, and RelB), which plays an essential role in inflammation and in the regulation of specific cellular functions such as apoptosis, proliferation, cell migration and metastasis. NF-κB plays an important role in preventing tumor cell apoptosis through the induction of anti-apoptotic genes such as the Inhibitors of Apoptosis (IAP) c-IAP1 and c-IAP2, or the melanoma inhibitor of apoptosis (ML-IAP) [4]. NF-κB controls the expression of several chemokines, interleukin IL-1 and IL-6, the vascular endothelial growth factor (VEGF), as well as other factors that are known to impact in MM progression [4]

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