ReviewEpigenetic silencing of 14-3-3sigma in cancer
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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2019, Environmental Toxicology and PharmacologyDNA methylation profiling in nonfunctioning pituitary adenomas
2018, Molecular and Cellular EndocrinologyCitation Excerpt :SFN encodes the 14-3-3σ protein which is a known tumor suppressor involved in TP53-dependent regulation of the cell cycle. Epigenetic inactivation of this gene was previously reported in tumors, mainly in those originating from epithelial tissues where SFN expression is the highest, i.e. melanomas, lung and prostate cancer and tumors of gastrointestinal tract (Lodygin and Hermeking, 2006). Epigenetic downregulation of SFN was also observed in tumors derived from tissues with a lower natural expression than in the pituitary gland: hepatocarcinoma, along with breast, ovarian, and endometrial tumors (Lodygin and Hermeking, 2006).
14-3-3σ regulates keratinocyte proliferation and differentiation by modulating yap1 cellular localization
2015, Journal of Investigative DermatologyThe p53 circuit board
2012, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :14-3-3σ was first identified as an epithelial cell antigen exclusively expressed in epithelia, and it is silenced via DNA methylation in many normal tissues [68]. In the context of cancer, 14-3-3σ, REPRIMO and miR-34a are common targets of aberrant silencing via DNA methylation, such that their availability varies across cancer cell types [69,70,110–117]. Furthermore, enhanced turnover of the p21 mRNA and impaired processing of the primary transcript for miR-34a prevent their accumulation upon p53 activation in some cell types [118].
14-3-3σ regulation by p53 mediates a chemotherapy response to 5-fluorouracil in MCF-7 breast cancer cells via Akt inactivation
2012, FEBS LettersCitation Excerpt :Cells lacking the 14-3-3σ function have impaired cell cycle control after DNA damage and increased genomic instability. Other studies have demonstrated that the loss or downregulation of 14-3-3σ expression is due to DNA hypermethylation rather than gene deletion or mutation [14,15]. In the progression of many human cancers, 14-3-3σ acts as a tumour suppressor.
14-3-3 proteins as signaling integration points for cell cycle control and apoptosis
2011, Seminars in Cell and Developmental Biology