Review
Epigenetic silencing of 14-3-3sigma in cancer

https://doi.org/10.1016/j.semcancer.2006.03.008Get rights and content

Abstract

The 14-3-3σ gene is a direct target of the p53 tumor suppressor and its product inhibits cell cycle progression. Recently, a proteomic analysis revealed that 14-3-3σ regulates additional cellular processes relevant to carcinogenesis, as migration and MAP-kinase signalling. The expression of 14-3-3σ is down-regulated by CpG methylation in several types of human cancer, among them prostate, lung, breast and several types of skin cancer. The epigenetic inactivation of 14-3-3σ occurs at an early stage of tumor development and may allow evasion from senescence and promote genomic instability. In the future the detection of CpG methylation of 14-3-3σ may be used for diagnostic and prognostic purposes.

Introduction

Cancer cells arise when mutations occur in critical regulatory genes [1], [2]. Point mutations or gene amplifications can result in the conversion of cellular proto-oncogenes into permanently activated oncogenes. Tumor suppressor genes are inactivated by point mutation, deletion, expression of viral oncogenes or by epigenetic silencing, which is mediated by methylation of CpG-residues in the respective promoter regions.

The tumor suppressor TP53 is presumably the most frequently altered gene in human cancer [3]. After DNA damage or deregulation of oncogenes p53 activates a transcriptional program which induces cell cycle arrest, programmed cell death and yet other tumor suppressive processes. Which of the outcomes of p53 activation occurs is determined by the cellular context [4]. Together with p21/CDKN1A, the 14-3-3σ gene belongs to a subset of p53 transcriptional targets whose activation promotes cell cycle arrest. The involvement of 14-3-3σ in the negative regulation of cell cycle progression and its frequent down-regulation in primary human tumors suggests that 14-3-3σ is an important mediator of p53's tumor suppressive function in vivo. Here we summarize and discuss the current literature on epigenetic silencing of 14-3-3σ and its possible implications for cancer biology and detection.

Section snippets

Epigenetic silencing in human cancer

Epigenetic mechanisms play an important role in gene expression and maintenance of genomic integrity (for comprehensive reviews see [5], [6], [7]). Among the molecules carrying epigenetic information, the methylation of 5′-cytosine within CpG dinucleotides, also referred to as DNA methylation, was identified first and its role in human disease has been studied intensely [8]. Clusters of CpG residues, also known as CpG islands, can be found in the 5′ regions of ∼60% of all human genes [9]. Most

Regulation and function of 14-3-3σ

14-3-3σ, or stratifin (SFN), belongs to a gene family which encodes seven different isoforms in mammalian cells. Like other 14-3-3 isoforms, the 14-3-3σ protein forms dimers and binds to protein ligands via a consensus binding motif phosphorylated on serine or threonine residues. The binding to 14-3-3 proteins can regulate the function of associated proteins through cytoplasmic sequestration, masking of interaction domains and export or import sequences, prevention of degradation, modulation of

Silencing of 14-3-3σ expression through CpG methylation in cancer cells

Initially, down-regulation of 14-3-3σ was detected in breast cancer cells by SAGE analysis [50]. However, no genetic alteration could be identified in the 14-3-3σ locus which would explain its decreased expression. Instead epigenetic silencing by CpG methylation turned out to be responsible for the loss or reduction of 14-3-3σ expression in more than 90% of ∼90 analyzed primary breast cancer samples [46]. Treatment of breast cancer cells with an inhibitor of DNA methyltransferases, 5Aza-2′dC,

Functional consequences of 14-3-3σ silencing in cancer

The high frequency of epigenetic silencing of 14-3-3σ in primary tumors suggests that the 14-3-3σ protein product is involved in tumor suppression. The loss of 14-3-3σ function most likely results in compromised cell cycle arrest and mitotic progression in the presence of un-repaired DNA damage. Since the inactivation of 14-3-3σ promotes the acquisition of chromosomal aberrations in vitro [48], the loss of 14-3-3σ expression in primary tumors presumably contributes to genomic instability. It

Predictive and diagnostic value of 14-3-3σ expression and methylation

Several recent publications indicate that the loss or retention of 14-3-3σ expression may have predictive value. For example, p53-positive esophageal squamous cell carcinomas, which express 14-3-3σ, show an improved histological response to combined radiation and chemotherapy [95]. Moreover, the survival rate after surgical treatment of patients with 14-3-3σ-positive tumors was higher than those with 14-3-3σ-negative tumors. The correlation between loss of 14-3-3σ protein and adverse clinical

Acknowledgements

Work in Heiko Hermeking's Lab is supported by the Max-Planck-Society.

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