FOXP3 Up-regulates <i>p21</i> Expression by Site-Specific Inhibition of Histone Deacetylase 2/Histone Deacetylase 4 Association to the Locus

Liu, Runhua; Wang, Lizhong; Chen, Guoyun; Katoh, Hiroto; Chen, Chong; Liu, Yang; Zheng, Pan

doi:10.1158/0008-5472.can-08-3717

Cited by 98 publications

(129 citation statements)

References 35 publications

(62 reference statements)

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“…Previous results have shown that class-IIa HDACs can control CDKN1A expression (Liu et al, 2009;Mottet et al, 2009;Saramaki et al, 2009;Wilson et al, 2008); however, the mechanisms involved are debated. MEF2-binding sites are present in the genomic regions surrounding CDKN1A.…”

Section: Discussionmentioning

confidence: 99%

The MEF2–HDAC axis controls proliferation of mammary epithelial cells and acini formation in vitro

Clocchiatti

Giorgio

Viviani

et al. 2015

Journal of Cell Science

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The myocyte enhancer factor 2 and histone deacetylase (MEF2-HDAC) axis is a master regulator of different developmental programs and adaptive responses in adults. In this paper, we have investigated the contribution of the axis to the regulation of epithelial morphogenesis, using 3D organotypic cultures of MCF10A cells as a model. We have demonstrated that MEF2 transcriptional activity is upregulated during acini formation, which coincides with exit from the proliferative phase. Upregulation of the transcription of MEF2 proteins is coupled to downregulation of HDAC7, which occurs independently from changes in mRNA levels, and proteasome-or autophagymediated degradation. During acini formation, the MEF2-HDAC axis contributes to the promotion of cell cycle exit, through the engagement of the CDK inhibitor CDKN1A. Only in proliferating cells can HDAC7 bind to the first intron of the CDKN1A gene, a region characterized by epigenetic markers of active promoters and enhancers. In cells transformed by the oncogene HER2 (ERBB2), acini morphogenesis is altered, MEF2 transcription is repressed and HDAC7 is continuously expressed. Importantly, reactivation of MEF2 transcriptional activity in these cells, through the use of a HER2 inhibitor or by enhancing MEF2 function, corrected the proliferative defect and re-established normal acini morphogenesis.

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Section: Discussionmentioning

confidence: 99%

The MEF2–HDAC axis controls proliferation of mammary epithelial cells and acini formation in vitro

Clocchiatti

Giorgio

Viviani

et al. 2015

Journal of Cell Science

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“…There is conflicting data on the relationship between p21 expression and outcome in breast cancer (138). The role of p21 in tamoxifen response has not been studied extensively, although the ERBB2 repressor forkhead box P3 is essential for p21 expression (143) and there is some evidence for p21 de-regulation in cancers with ERBB2 over-expression or AKT activation (139). The latter results in the mis-localization of p21 to the cytoplasm, a phenomenon associated with poor response to tamoxifen (144).…”

Section: Co-activators and Co-repressorsmentioning

confidence: 99%

Signalling pathways involved in endocrine resistance in breast cancer and associations with epithelial to mesenchymal transition (Review)

Saleh

Sharaf²,

Luqmani

2011

Int J Oncol

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Abstract. Both de novo and acquired endocrine resistance constitute a major therapeutic problem for treatment of hormone-positive breast cancer. Multiple explanatory mechanisms have been proposed through the study of cellular models which focus principally on receptor tyrosine kinase mediated signalling pathways utilizing sRC, PI3K, MAPK and sMAds. Many of the transducing molecules, particularly nuclear transcription factors such as sNAIL, TwIsT, sNAIL2, ZEB, FOXC2, TCF/LEF and GOOsECOId are participants in proliferation as well as invasion and metastasis, involving a process of orchestrated cellular remodeling which is being likened to the process of epithelial to mesenchymal transition that takes place during embryonic development. we review the accumulating evidence that points towards the occurrence of this phenomenon as a consequence of the loss of endocrine control, with both processes being similarly characterized by depletion of cell adhesion proteins, E-cadherin, catenins and cytokeratins, increased association with the extracellular matrix through induction of metalloproteinases, fibronectin and collagen, and a switch to a mobile vimentin-based cytoskeletal structure with loss of apical basal polarity. IntroductionEndocrine therapy represents the most effective form of treatment for the majority of breast cancer patients whose tumours over-express the estrogen receptor (ER). In addition to ablative procedures (ovariectomy) and administration of antiendocrine agents to inhibit ovarian function, treatment is reliant predominantly upon anti-hormonal agents termed selective estrogen modulators (sERMs). Until recent introduction of agents such as toremifene and raloxifene, tamoxifen has been the mainstay of treatment (1) inducing objective response or disease stabilization in over half of previously untreated metastatic breast cancer patients with ER + tumours (2). Further options include the use of pure anti-estrogens such as fulvestrant (Faslodex) which achieves its effects through receptor degradation, and application of aromatase inhibitors that reduce extra-gonadal peripheral estrogen synthesis from the adrenals and adipose tissue, including the breast. Both types of agents improve relapse-free survival and reduce incidence of contralateral breast cancers in women with early-stage cancer and increase overall survival in patients with advanced disease (3,4). Unfortunately, following initial response to sERMs and second line therapy with aromatase inhibitors, most patients subsequently develop resistance to both classes of drugs and become refractive to further attempts at endocrine manipulation. Added to the de novo resistance in patients whose tumours express levels of ER <10 fmol/mg protein, this presents a serious therapeutic problem, particularly in view of the increased aggressiveness of hormone insensitive breast cancers. Estrogen receptor actionThe classical mode of action of ER is related to the regulation of expression of genes with estrogen response elements (ERE) in their promoters through t...

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“…For example, FOXP3 directly represses the ERBB2 and SKP2 oncogenes while maintaining the expression of the p21 tumour suppressor in the breast epithelium (Zuo et al, 2007a, b;Liu et al, 2009). In prostate cells, FOXP3 has also been shown to directly repress c-myc transcription , an oncogene frequently overexpressed in many human cancers (Wolfer et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

FOXP3 and FOXP3-regulated microRNAs suppress SATB1 in breast cancer cells

et al. 2011

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The transcription factor FOXP3 has been identified as a tumour suppressor in the breast and prostate epithelia, but little is known about its specific mechanism of action. We have identified a feed-forward regulatory loop in which FOXP3 suppresses the expression of the oncogene SATB1.In particular, we demonstrate that SATB1 is not only a direct target of FOXP3 repression, but that FOXP3 also induces two miRs, miR-7 and miR-155, which specifically target the 3 0 -UTR of SATB1 to further regulate its expression. We conclude that FOXP3-regulated miRs form part of the mechanism by which FOXP3 prevents the transformation of the healthy breast epithelium to a cancerous phenotype. Approaches aimed at restoring FOXP3 function and the miRs it regulates could help provide new approaches to target breast cancer.

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FOXP3 Up-regulates p21 Expression by Site-Specific Inhibition of Histone Deacetylase 2/Histone Deacetylase 4 Association to the Locus

Cited by 98 publications

References 35 publications

The MEF2–HDAC axis controls proliferation of mammary epithelial cells and acini formation in vitro

The MEF2–HDAC axis controls proliferation of mammary epithelial cells and acini formation in vitro

Signalling pathways involved in endocrine resistance in breast cancer and associations with epithelial to mesenchymal transition (Review)

FOXP3 and FOXP3-regulated microRNAs suppress SATB1 in breast cancer cells

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