Absence of p300 induces cellular phenotypic changes characteristic of epithelial to mesenchyme transition

Krubasik, Davia; Iyer, N. Gopalakrishna; English, William R.; Ahmed, Aamir; Vias, Maria; Roskelley, Calvin D.; Brenton, James D.; Caldas, Carlos; Murphy, Gillian

doi:10.1038/sj.bjc.6603101

Cited by 42 publications

(51 citation statements)

References 16 publications

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“…43 In addition, somatic mutations in EP300 have been identified in several malignancies. 44 Importantly, EP300-deficient colon carcinoma cells show phenotypic changes characteristic of EMT, 45 in line with the results reported here. The involvement of miRs in drug resistance, CSCs (cells originated from adult stem cells, which have acquired tumorigenic properties and drive tumor growth and progression because of their unlimited proliferative potential), and EMT is now well established.…”

Section: Discussionsupporting

confidence: 79%

The miR-106b∼25 cluster promotes bypass of doxorubicin-induced senescence and increase in motility and invasion by targeting the E-cadherin transcriptional activator EP300

Zhou

Yang

et al. 2013

Cell Death Differ

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Resistance to chemotherapeutic treatment, which is indirectly responsible for many cancer deaths, is normally associated with an aggressive phenotype including increased cell motility and acquisition of invasive properties. Here we describe how breast cancer cells overcome doxorubicin-induced senescence and become drug resistant by overexpression of the microRNA (miR)-106bB25 cluster. Although all three miRs in the cluster contribute to the generation of doxorubicin resistance, miR-25 is the major contributor to this phenotype. All three miRs in this cluster target EP300, a transcriptional activator of E-cadherin, resulting in cells acquiring a phenotype characteristic of cells undergoing epithelial-to-mesenchymal transition (EMT), including an increase in both cell motility and invasion, as well as the ability to proliferate after treatment with doxorubicin. These findings provide a novel drug resistance/EMT regulatory pathway controlled by the miR-106bB25 cluster by targeting a transcriptional activator of E-cadherin.

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Section: Discussionsupporting

confidence: 79%

The miR-106b∼25 cluster promotes bypass of doxorubicin-induced senescence and increase in motility and invasion by targeting the E-cadherin transcriptional activator EP300

Zhou

Yang

et al. 2013

Cell Death Differ

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“…Mutations and deletions of p300 have been observed in a variety of cancers (Iyer et al, 2004). Recent studies of p300-null HCT116 cells indicate that p300-null cells show loss of cell-to-cell adhesion, defects in cell-matrix adhesion and increased migration (Krubasik et al, 2006). Our studies now show that p300 is responsible for acetylation of cortactin, thus providing mechanistic insights into enhanced cell migration in p300-null cells.…”

Section: Discussionmentioning

confidence: 65%

Deacetylation of cortactin by SIRT1 promotes cell migration

et al. 2008

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Cortactin binds F-actin and promotes cell migration. We showed earlier that cortactin is acetylated. Here, we identify SIRT1 (a class III histone deacetylase) as a cortactin deacetylase and p300 as a cortactin acetylase. We show that SIRT1 deacetylates cortactin in vivo and in vitro and that the SIRT1 inhibitor EX-527 increases amounts of acetylated cortactin in ovarian cancer cells. We also show that p300 acetylates cortactin in vivo and that cells lacking or depleted of p300 express lessacetylated cortactin than do control cells. Deletion analysis mapped the SIRT1-binding domain of cortactin to its repeat region, which also binds F-actin. Mouse embryo fibroblasts (MEFs) lacking sir2a (the mouse homolog of SIRT1) migrated more slowly than did wildtype cells. The expression of SIRT1 in sir2a-null cells restored migratory capacity, as did expression of a deacetylation-mimetic mutant of cortactin. SIRT1 and cortactin were more abundant in breast tumor tissue than in their normal counterparts, whereas SIRT1 expression inversely correlates with the ratio of acetylation cortactin versus total cortactin. These data suggest that deacetylation of cortactin is associated with high levels of SIRT1 and tumorigenesis. Finally, breast and ovarian cancer cell lines expressing an acetylation mimetic mutant of cortactin are less motile than that of control cells, whereas cells expressing the deacetylation mimetic mutant of cortactin migrate faster than that of control cells in Transwell migration assays. In summary, our results suggest that cortactin is a novel substrate for SIRT1 and p300 and, for the first time, a possible role for SIRT1 in cell motility through deacetylation of cortactin.

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“…suppressors). 32 As an example, at least 4 of these are located at those chromosomal loci significantly associated with pN in this study, such as Maspin 31 at 18q21.3 (D18S858), EP300 33 at 22q13 (D22S1045), and PLCB1 34 at D20S851, as well as MYH9 35 on D22S683, which are known to be associated with metastasis, invasion, or both. In particular, EP300 encodes p300, which is a transcriptional cofactor and prototype histone acetyltransferase that plays a role in multiple cellular processes.…”

Section: Sporadic Primary Invasive Breast Carcinomasmentioning

confidence: 99%

“…In vitro, p300-deficient cells appeared to have an aggressive phenotype with loss of cellcell adhesion and defects in cell-matrix adhesion. 33 In vivo, embryos lacking p300 were shown to arrest development and die between E8.5 and E11, suggesting that p300 would be necessary for healthy organ development. 36 Our observation might also explain why epigenetic phenomena are more prominent in tumor stroma.…”

Section: Sporadic Primary Invasive Breast Carcinomasmentioning

confidence: 99%

Genomic Instability Within Tumor Stroma and Clinicopathological Characteristics of Sporadic Primary Invasive Breast Carcinoma

Fukino¹,

Shen²,

Patócs³

et al. 2007

JAMA

102

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A HIGH DEGREE OF VARIABILITY IS observed in both biological behavior and clinical outcome in sporadic breast cancer, and this interpatient diversity in breast cancer biology and behavior may confound clinical management based on averages. Breast conserving surgery has become the standard of care for early stage breast cancer. In a recently published study, 2929 patients with early stage breast cancer were examined for the relative impact of the patient, the surgeon, hospital factors, or all 3 on surgical treatment outcome variation in patients with breast cancer. The study by Gort et al 1 showed that 91.2% of the total variance was attributable to the patient level (there was large interpatient variability). These data suggested that interpatient variation accounts for the high degree of clinical variability. Indeed, the demand for personalized medicine illustrates the medical community's and public's recognition of interpatient variability. It has been recognized for decades that identical chemotherapeutic regimens for similar stage and grade in patients with, for example, breast cancer (or virtually any malignancy) respond differently. Context That genomic alterations occur in both the epithelium and stroma of sporadic breast cancers has been documented by several groups. However, whether these microenvironmental alterations relate to clinicopathological features is unknown.Objective To analyze the relationship between stromal genomic alterations and presenting clinicopathological features in sporadic breast cancer. Main Outcome Measures Association of the loss of heterozygosity/allelic imbalance, in both the stroma and epithelium, with presenting clinicopathological features, such as tumor grade, expression status of estrogen receptor and progesterone receptor, human epidermal growth factor receptor 2, clinical stage, and regional lymph node metastasis status. Associations were assessed in regression models and tested with Fisher exact test. Bonferroni correction was applied to P values, with significance set at PϽ.0022. Design, Setting, and Participants

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Absence of p300 induces cellular phenotypic changes characteristic of epithelial to mesenchyme transition

Cited by 42 publications

References 16 publications

The miR-106b∼25 cluster promotes bypass of doxorubicin-induced senescence and increase in motility and invasion by targeting the E-cadherin transcriptional activator EP300

The miR-106b∼25 cluster promotes bypass of doxorubicin-induced senescence and increase in motility and invasion by targeting the E-cadherin transcriptional activator EP300

Deacetylation of cortactin by SIRT1 promotes cell migration

Genomic Instability Within Tumor Stroma and Clinicopathological Characteristics of Sporadic Primary Invasive Breast Carcinoma

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