A “Twist box” Code of p53 Inactivation: Twist box:p53 Interaction Promotes p53 Degradation

Piccinin, Sara; Tonin, Elena; Sessa, Sara; Demontis, Silvia; Rossi, Sabrina; Pecciarini, Lorenza; Zanatta, Lucia; Pivetta, Flavia; Grizzo, Alessandra; Sonego, Maura; Rosano, Camillo; Tos, Angelo Paolo Dei; Doglioni, Claudio; Maestro, Roberta

doi:10.1016/j.ccr.2012.08.003

Cited by 107 publications

(128 citation statements)

References 56 publications

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“…In particular, the switch from DFSP to FS-DFSP was paralleled by an enrichment in genes belonging to the EMT gene signature, as defined by Gr€ oger and colleagues (15). The EMT program has been linked to aggressive tumor behavior, and modulation of mesenchymal traits toward a more undifferentiated state has been previously reported to play a pivotal role in sarcoma development and progression (16)(17)(18)(19)(20)(21). EMT is governed by a set of transcription factors, including TWIST1, SNAI2/SLUG, and ZEB1.…”

Section: Discussionmentioning

confidence: 97%

Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial–Mesenchymal Transition–like Process and 22q Loss

Stacchiotti

Astolfi

Gronchi

et al. 2016

Molecular Cancer Research

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Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma. At times, a fibrosarcomatous transformation marked by a more aggressive clinical behavior may be present. We investigated the natural history and the molecular bases of progression from classic DFSP to the fibrosarcomatous form (FS-DFSP), looking, retrospectively, at the outcome of all patients affected by primary DFSP treated at our institution from 1993 to 2012 and analyzing the molecular profile of 5 DFSPs and 5 FS-DFSPs by an integrated genomics approach (whole transcriptome sequencing, copy number analysis, FISH, qRT-PCR, IHC). The presence of fibrosarcomatous features was identified in 20 (7.6%) patients out of 263 DFSP. All cases were treated with macroscopic complete surgery. A local relapse occurred in 4 of 23 patients who received a microscopic marginal surgery (2 classic DFSP, 2 FS-DFSP), while metastasis affected 2 patients, both FS-DFSP (10% of FS-DFSP), being the first event. DFSP evolution to FS-DFSP was paralleled by a transcriptional reprogramming. The recurrent loss of chromosome 22q appeared to contribute to this phenomenon by promoting the expression of epigenetic regulators, such as EZH2. Loss of the p16/CDKN2A/INK4A locus at 9p was also observed in two FS-DFSP metastatic cases.Implications: FS-DFSP is a rare subgroup among DFSP, with a 10% metastatic risk, that was independent from local recurrence and that was not observed in DFSP, that were all cured by wide surgery. Chromosome 22q deletion might play a role in FS-DFSP, and p16 loss may convey a poor outcome. EZH2 dysregulation was also found and represents a druggable target.

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Section: Discussionmentioning

confidence: 97%

Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial–Mesenchymal Transition–like Process and 22q Loss

Stacchiotti

Astolfi

Gronchi

et al. 2016

Molecular Cancer Research

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“…Twist1 was also shown to override oncogene-induced senescence and apoptosis by binding to p53 and promoting its degradation (Valsesia-Wittmann et al 2004;Ansieau et al 2008;Lee and Bar-Sagi 2010;Piccinin et al 2012). By inhibiting p53, Twist1 was able to cooperate with oncogenes such as Her2 and H-ras to promote malignant transformation (Valsesia-Wittmann et al 2004;Ansieau et al 2008;Morel et al 2012;Piccinin et al 2012), suggesting a potential role of EMT genes in tumor initiation.…”

Section: Malignant Conversionmentioning

confidence: 96%

Epithelial–mesenchymal plasticity in carcinoma metastasis

2013

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Tumor metastasis is a multistep process by which tumor cells disseminate from their primary site and form secondary tumors at a distant site. Metastasis occurs through a series of steps: local invasion, intravasation, transport, extravasation, and colonization. A developmental program termed epithelial-mesenchymal transition (EMT) has been shown to play a critical role in promoting metastasis in epithelium-derived carcinoma. Recent experimental and clinical studies have improved our knowledge of this dynamic program and implicated EMT and its reverse program, mesenchymal-epithelial transition (MET), in the metastatic process. Here, we review the functional requirement of EMT and/or MET during the individual steps of tumor metastasis and discuss the potential of targeting this program when treating metastatic diseases.Epithelial and mesenchymal cell types have long been recognized by their unique cell morphology and organization in tissues. Epithelial cells form polarized sheets or layers of cells that are connected laterally via several types of cellular junctions, including adherens junctions, desmosomes, and tight junctions. In addition, epithelial cells anchor themselves to the underlying basement membrane via hemidesmosomes to maintain apical-basal polarity. Both desmosomes and hemidesmosomes further connect with the epithelial-specific cytokeratin intermediate filaments. In contrast, mesenchymal cells embed themselves inside the extracellular matrix (ECM) and rarely establish tight contact with neighboring cells. During specific embryonic morphogenesis processes such as mesoderm formation and neural crest development, epithelial cells can exhibit enormous plasticity and transit into a mesenchymal state by activating the epithelial-mesenchymal transition (EMT) program. After EMT, these cells lose their epithelial junctions and switch to producing vimentin filaments. The functional hallmark of the EMT program is to allow stationary epithelial cells to gain the ability to migrate and invade during developmental morphogenesis (Boyer and Thiery 1993;Hay 1995).Although epithelial cells convert into the mesenchymal state during developmental EMT, entering the EMT program is not necessarily an irreversible commitment, as evident during kidney tubule formation. These epithelial cells can activate a transitory EMT program and then undergo a reverse process called mesenchymal-epithelial transition (MET) to continue their differentiation paths (Thiery et al. 2009;Lim and Thiery 2012). In many instances, the identification of an epithelial versus a mesenchymal state can be relatively fluid, and a partial EMT/MET frequently occurs to fulfill unique developmental tasks. These dynamic EMT/MET events highlight the enormous flexibility of presumably differentiated cells during morphogenesis.In the past decade, an increasing number of studies have provided strong evidence for the reinitiation of the EMT developmental program in carcinoma progression and metastasis. This EMT program in tumor metastasis possesses many morpholog...

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“…BALB/c 3T3 cells were generated from BALB/c primary MEF using the 3T3 protocol (28) and were grown in DMEM supplemented with 10% calf serum. The human leiomyosarcoma cell lines SKUT-1, DMR, and SK-LMS1 were cultivated as previously described (42). For analyses of cell growth, 10 4 cells were seeded, and the medium was changed every 2 days.…”

Section: Methodsmentioning

confidence: 99%

MEF2 Is a Converging Hub for Histone Deacetylase 4 and Phosphatidylinositol 3-Kinase/Akt-Induced Transformation

Giorgio

Clocchiatti

Piccinin

et al. 2013

Molecular and Cellular Biology

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The MEF2-class IIa histone deacetylase (HDAC) axis operates in several differentiation pathways and in numerous adaptive responses. We show here that nuclear active HDAC4 and HDAC7 display transforming capability. HDAC4 oncogenic potential depends on the repression of a limited set of genes, most of which are MEF2 targets. Genes verified as targets of the MEF2-HDAC axis are also under the influence of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway that affects MEF2 protein stability. A signature of MEF2 target genes identified by this study is recurrently repressed in soft tissue sarcomas. Correlation studies depicted two distinct groups of soft tissue sarcomas: one in which MEF2 repression correlates with PTEN downregulation and a second group in which MEF2 repression correlates with HDAC4 levels. Finally, simultaneous pharmacological inhibition of the PI3K/Akt pathway and of MEF2-HDAC interaction shows additive effects on the transcription of MEF2 target genes and on sarcoma cells proliferation. Overall, our work pinpoints an important role of the MEF2-HDAC class IIa axis in tumorigenesis.

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A “Twist box” Code of p53 Inactivation: Twist box:p53 Interaction Promotes p53 Degradation

Cited by 107 publications

References 56 publications

Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial–Mesenchymal Transition–like Process and 22q Loss

Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial–Mesenchymal Transition–like Process and 22q Loss

Epithelial–mesenchymal plasticity in carcinoma metastasis

MEF2 Is a Converging Hub for Histone Deacetylase 4 and Phosphatidylinositol 3-Kinase/Akt-Induced Transformation

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