The role of epigenetic inactivation of 14-3-3σ in human cancer

Lodygin, Dmitri; Hermeking, Heiko

doi:10.1038/sj.cr.7290292

Cited by 72 publications

(68 citation statements)

References 69 publications

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“…For example, the estrogen-regulated E3 ubiquitin ligase Efp can specifically downregulate 14-3-3σ and promote breast cancer growth through proteolytic degradation (40). The emerging role of 14-3-3σ as a potent tumor suppressor in many cancers is further supported by the identification of the methylation-dependent silencing of 14-3-3σ in prostate, melanoma, vulval, and salivary tumors (41). Collectively, these observations implicate 14-3-3σ as a major tumor suppressor in a number of human malignancies.…”

Section: Discussion Loss Of 14-3-3s Is a Critical Event In Erbb2 Mammmentioning

confidence: 80%

Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression

Chen

Zuo

et al. 2012

Cancer Discovery

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is a putative tumor suppressor involved in cell-cycle progression and epithelial polarity. We demonstrate that loss of one or both copies of the conditional 14-3-3σ allele results in accelerated mammary and salivary tumorigenesis in mice expressing an activated erbB2 oncogene under the endogenous erbB2 promoter. Significantly, the majority of tumors bearing a single conditional 14-3-3σ allele lose expression of the remaining 14-3-3σ allele, which is associated with epigenetic methylation of the 14-3-3σ locus. In addition to accelerated tumor onset, in a mouse mammary tumor virusdriven ErbB2 tumor model, loss of 14-3-3σ results in enhanced metastatic phenotype that is correlated with loss of cellular junctions. Taken together, these results provide compelling evidence that 14-3-3σ is a potent tumor suppressor involved in ErbB2-driven breast cancer initiation and metastasis.siGNiFicaNce: 14-3-3σ has been identified as a normal mammary epithelial cell marker frequently downregulated during neoplastic development. Consistent with its potential role as a tumor suppressor, we demonstrate that targeted disruption of 14-3-3σ in a number of epithelial tissues can profoundly impact both the initiation and metastatic phases of ErbB2-mediated tumor progression through modulation of a number of distinct signaling networks. Cancer Discovery; 2(1); 68-81.

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Section: Discussion Loss Of 14-3-3s Is a Critical Event In Erbb2 Mammmentioning

confidence: 80%

Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression

Chen

Zuo

et al. 2012

Cancer Discovery

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“…The overexpression of these genes was associated with chromosome instability, suggesting that 1q and 11q gains increase the chromosome instability-related genes. 42 Among the downexpressed genes mapping at lost chromosome regions (1p36.11-36.33 and 3p24.1-26.3), we underline that the SFN and RAD18 genes play a key role in the prevention of cell malignant transformation 43,44 and may contribute to increase the chromosome instability observed in tumors of high-risk patients. Interestingly, the protein analysis demonstrated a low level of RAD18 expression in G3, unless in two of four G3/MYCNþ.…”

Section: Discussionmentioning

confidence: 87%

Age‐dependent accumulation of genomic aberrations and deregulation of cell cycle and telomerase genes in metastatic neuroblastoma

Coco

Theißen

Scaruffi

et al. 2012

Intl Journal of Cancer

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About 50% of children with neuroblastoma (NB) show a metastatic disease and have a poor prognosis. However, disease progression is greatly variable and depends on patients' age and MYCN oncogene amplification. To investigate the role of patients' age in tumor aggressiveness, we performed array-CGH and gene expression profiles of three groups (G) of metastatic NBs: G1, stage 4S patients and MYCN single copy (MYCN-) tumors; G2, stage 4 patients, ≤18 months of age, MYCN- tumors and favorable outcome and G3, Stage 4 patients, a19 months with unfavorable outcome. G1 was characterized by numerical aberrations prevalently; on the contrary, all G3 tumors had structural rearrangements, whereas G2 showed an intermediate pattern. The average of numerical alterations decreased significantly from G1 to G2 to G3 (p < 0.01). Contrarily, the number of structural aberrations increased from G1 to G2 to G3 (p< 2.35 E-05). Noteworthy, G3/MYCN- NBs were characterized by several complex intrachromosome rearrangements. Expression analysis of the three groups showed significant differences in genes of Rho and Ras signaling pathways, development and adhesion, cell cycle regulation and telomerase activity. Accumulation of structural alterations increased with patients' age and was associated with a more aggressive disease. Abnormal expression of genes involved in cell cycle and telomerase in G3 may be responsible for the genomic instability in this cohort of patients. The higher DNA instability observed in G3/MYCN- NBs than in MYCN-amplified G3 may also explain why patients a19 months have a poor outcome independently by MYCN status. Copyright © 2012 UICC

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“…Lastly, silencing of the 14-3-3σ gene occurs by CpG methylation, and it is seen in various cancers 14-4-3σ σ σ σ σ AND CANCER 14-3-3σ is a tumor suppressor gene, which contributes to cancer development. Gene silencing of 14-3-3σ, mainly by CpG methylation, occurs in numerous solid tumor types and even in hematologic malignancies (also see review in the same issue by Lodygin and Hermeking) [52]. There is a significant association between aberrant 14-3-3σ protein expression (as shown by immunohistochemistry (IHC) and CpG methylation detected by methylation specific-PCR (MSP).…”

Section: -3-3 In Cell Spreading and Migrationmentioning

confidence: 99%

14-3-3 proteins—an update

2005

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ABSTRACT14-3-3 is a highly conserved acidic protein family, composed of seven isoforms in mammals. 14-3-3 protein can interact with over 200 target proteins by phosphoserine-dependent and phosphoserine-independent manners. Little is known about the consequences of these interactions, and thus are the subjects of ongoing studies. 14-3-3 controls cell cycle, cell growth, differentiation, survival, apoptosis, migration and spreading. Recent studies have revealed new mechanisms and new functions of 14-3-3, giving us more insights on this fascinating and complex family of proteins. Of all the seven isoforms, 14-3-3σ seems to be directly involved in human cancer. 14-3-3σ itself is subject to regulation by p53 upon DNA damage and by epigenetic deregulation. Gene silencing of 14-3-3σ by CpG methylation has been found in many human cancer types. This suggests that therapy-targeting 14-3-3σ may be beneficial for future cancer treatment.

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The role of epigenetic inactivation of 14-3-3σ in human cancer

Cited by 72 publications

References 69 publications

Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression

Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression

Age‐dependent accumulation of genomic aberrations and deregulation of cell cycle and telomerase genes in metastatic neuroblastoma

14-3-3 proteins—an update

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