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Targeting the SIN3A-PF1 Interaction inhibits Epithelial to Mesenchymal Transition and Maintenance of a Stem Cell Phenotype in Triple Negative Breast Cancer (Expression)

ABSTRACT: Triple negative breast cancer (TNBC) is characterized by a poorly differentiated phenotype and limited treatment options. Aberrant epigenetics in this subtype represent a potential therapeutic opportunity, but a better understanding of the mechanisms contributing to the TNBC pathogenesis is required. The SIN3 molecular scaffold performs a critical role in multiple cellular processes, including epigenetic regulation, and has been identified as a potential therapeutic target. Using a competitive peptide corresponding to the SIN3 interaction domain of MAD (Tat-SID), we investigated the functional consequences of selectively blocking the paired amphipathic helix (PAH2) domain of SIN3. Here, we report the identification of the SID-containing adaptor PF1 as a factor required for maintenance of the TNBC stem cell phenotype and epithelial to mesenchymal transition (EMT). Tat-SID peptide blocked the interaction between SIN3A and PF1, leading to epigenetic modulation and transcriptional downregulation of TNBC stem cell and EMT markers. Importantly, Tat-SID treatment led to a reduction in primary tumor growth and disseminated metastatic disease in vivo. In support of these findings, knockdown of PF1 expression phenocopied treatment with Tat-SID both in vitro and in vivo. These results demonstrate a critical role for a complex containing SIN3A and PF1 in TNBC and provide a rational for its therapeutic targeting.

ORGANISM(S): Homo sapiens

PROVIDER: GSE73278 | GEO | 2015/11/02

SECONDARY ACCESSION(S): PRJNA296515

REPOSITORIES: GEO

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Targeting the SIN3A-PF1 Interaction inhibits Epithelial to Mesenchymal Transition and Maintenance of a Stem Cell Phenotype in Triple Negative Breast Cancer (Expression)

Project description:Triple negative breast cancer (TNBC) is characterized by a poorly differentiated phenotype and limited treatment options. Aberrant epigenetics in this subtype represent a potential therapeutic opportunity, but a better understanding of the mechanisms contributing to the TNBC pathogenesis is required. The SIN3 molecular scaffold performs a critical role in multiple cellular processes, including epigenetic regulation, and has been identified as a potential therapeutic target. Using a competitive peptide corresponding to the SIN3 interaction domain of MAD (Tat-SID), we investigated the functional consequences of selectively blocking the paired amphipathic helix (PAH2) domain of SIN3. Here, we report the identification of the SID-containing adaptor PF1 as a factor required for maintenance of the TNBC stem cell phenotype and epithelial to mesenchymal transition (EMT). Tat-SID peptide blocked the interaction between SIN3A and PF1, leading to epigenetic modulation and transcriptional downregulation of TNBC stem cell and EMT markers. Importantly, Tat-SID treatment led to a reduction in primary tumor growth and disseminated metastatic disease in vivo. In support of these findings, knockdown of PF1 expression phenocopied treatment with Tat-SID both in vitro and in vivo. These results demonstrate a critical role for a complex containing SIN3A and PF1 in TNBC and provide a rational for its therapeutic targeting. Sub-confluent cultures of MDA-MB-231 cells were treated with 1ÂµM Tat-SID peptide or 1ÂµM Tat-Scr scrambled control peptide for 24hr.

2015-11-02 | E-GEOD-73278 | biostudies-arrayexpress

Targeting the SIN3A-PF1 Interaction inhibits Epithelial to Mesenchymal Transition and Maintenance of a Stem Cell Phenotype in Triple Negative Breast Cancer (MNase-seq)

Project description:Triple negative breast cancer (TNBC) is characterized by a poorly differentiated phenotype and limited treatment options. Aberrant epigenetics in this subtype represent a potential therapeutic opportunity, but a better understanding of the mechanisms contributing to the TNBC pathogenesis is required. The SIN3 molecular scaffold performs a critical role in multiple cellular processes, including epigenetic regulation, and has been identified as a potential therapeutic target. Using a competitive peptide corresponding to the SIN3 interaction domain of MAD (Tat-SID), we investigated the functional consequences of selectively blocking the paired amphipathic helix (PAH2) domain of SIN3. Here, we report the identification of the SID-containing adaptor PF1 as a factor required for maintenance of the TNBC stem cell phenotype and epithelial to mesenchymal transition (EMT). Tat-SID peptide blocked the interaction between SIN3A and PF1, leading to epigenetic modulation and transcriptional downregulation of TNBC stem cell and EMT markers. Importantly, Tat-SID treatment led to a reduction in primary tumor growth and disseminated metastatic disease in vivo. In support of these findings, knockdown of PF1 expression phenocopied treatment with Tat-SID both in vitro and in vivo. These results demonstrate a critical role for a complex containing SIN3A and PF1 in TNBC and provide a rational for its therapeutic targeting. Mononucleosomes from MDA-MB-231 cells were isolated and ChIP with H3K4me3 antibody. DNA from Input and ChIP samples was purified and sequenced on Illumina Hiseq.

2015-11-02 | E-GEOD-73869 | biostudies-arrayexpress

Targeting the SIN3A-PF1 Interaction inhibits Epithelial to Mesenchymal Transition and Maintenance of a Stem Cell Phenotype in Triple Negative Breast Cancer (MNase-seq)

2015-11-02 | GSE73869 | GEO

Selective inhibition of SIN3 corepressor with avermectins as a novel therapeutic strategy in triple negative breast cancer

Project description:Triple negative breast cancers (TNBC) lacking estrogen, progesterone and HER2 receptors account for 10-20% of breast cancer and are indicative of poor prognosis. The development of effective treatment strategies therefore represents a pressing unmet clinical need. We previously identified a molecularly-targeted approach to target aberrant epigenetics of TNBC using a peptide corresponding to the SIN3 interaction domain (SID) of MAD. SID peptide selectively blocked binding of SID-containing proteins to the paired α-helix (PAH2) domain of SIN3, resulting in epigenetic and transcriptional modulation of genes associated with epithelial-mesenchymal transition (EMT). To find small molecule inhibitor (SMI) mimetics of SID peptide we performed an in silico screen for PAH2 domain-binding compounds. This led to the identification of the avermectin macrocyclic lactone derivatives selamectin and ivermectin (Mectizan) as candidate compounds. Both selamectin and ivermectin phenocopied the effects of SID peptide to block SIN3-PAH2 interaction with MAD, induce expression of CDH1 and ESR1 and restore tamoxifen sensitivity in MDA-MB-231 human and MMTV-Myc mouse TNBC cells in vitro. Treatment with selamectin or ivermectin led to transcriptional modulation of genes associated with EMT and maintenance of a cancer stem cell phenotype in TNBC cells. This resulted in impairment of clonogenic self-renewal in vitro and inhibition of tumor growth and metastasis in vivo. Underlining the potential of avermectins in TNBC, pathway analysis revealed that selamectin also modulated the expression of therapeutically-targetable genes. Consistent with this, an unbiased drug screen in TNBC cells identified selamectin-induced sensitization to a number of drugs, including those targeting modulated genes.

2015-06-01 | GSE67438 | GEO

Targeted interference of sin3a-tgif1 function by SID decoy treatment inhibits WNT signaling and invasion in triple negative breast cancer cells

Project description:Targeted interference of sin3a-tgif1 function by SID decoy treatment inhibits WNT signaling and invasion in triple negative breast cancer cells. MDA-MB-231 cells were treated with scrambled SID control, 2.5ÂµM SID peptide or untreated for 24h. Sub-confluent cultures of MDA-MB-231 cells were treated with scrambled SID control, 2.5ÂµM SID peptide or untreated for 24h. Experiments were performed as three independent replicates.

2016-07-21 | E-GEOD-84648 | biostudies-arrayexpress

Targeted interference of sin3a-tgif1 function by SID decoy treatment inhibits WNT signaling and invasion in triple negative breast cancer cells

2016-07-21 | GSE84648 | GEO

Genome-wide maps of Sin3A and Sin3B binding in C2C12 myoblasts and differentiated myotubes

Project description:Sin3A and Sin3B bind to distinct and overlapping target sites. Sin3 proteins bind to distinct sites in cycling myoblasts whereas there is a converge of Sin3A and Sin3B proteins to sites in differentiated myotubes. We identified a subset of Sin3 target genes involved in muscle differentiation and physiology and showed that conditional ablation of Sin3 proteins in vivo in mouse results in sarcomere defects Examination of Sin3A and Sin3B binding during myogenesis

2011-01-01 | E-GEOD-22554 | biostudies-arrayexpress

Genome-wide maps of Sin3A and Sin3B binding in C2C12 myoblasts and differentiated myotubes

2011-01-01 | GSE22554 | GEO

The chromatin associated Pf1 protein maintains nucleolar integrity: gene expression from Pf1 +/+ and Pf1-/- mouse embryonic fibroblasts.

Project description:Pf1, also known as Phf12 (plant homeodomain (PHD) zinc finger protein 12) is a member of the PHD zinc finger family. Pf1 was first identified in a yeast-two hybrid screen for proteins interacting with the paired amphipathic helix (PAH) 2 domain of mSin3A, and shown to function as a transcriptional repressor . We generated Pf1 knockout mice to define the physiological role of Pf1. To identify the molecular mechanisms underlying the cellular defects elicited by genetic inactivation of Pf1, we next examined the impact of a Pf1 deletion on genome-wide transcriptome. RNA extracted from wild-type and Pf1-depleted MEFs was profiled by hybridization to a whole genome microarray.

2017-01-10 | GSE86398 | GEO

Transcriptome analysis upon SIN3 or dKDM5/LID knockdown or both under normal and paraquat induced stress conditions in Drosophila S2 cultured cells

Project description:SIN3 the scaffold protein of a histone deacetylase complex interacts with a histone demethylase KDM5 (little imaginal discs - LID) in Drosophila. Reduction of SIN3 or dKDM5/LID both result in similar phenotypes during cell proliferation and wing development. To identify underlying transcriptional changes that may contribute to these phentypic defects we performed whole genome expression analysis in Drosophila cultured cells upon RNAi-mediated knockdown of Sin3A, lid or both. We identified a large number of genes regulated by SIN3, dKDM5/LID or both. While many common genes were regulated by SIN3 and dKDM5/LID an enrichment for genes involved in stress tolerance pathways was observed. Additional RNAseq analysis of expression changes upon knockdown of Sin3A, lid or both under paraquat mediated oxidative stress conditions identified significant changes in genes involved in cell cycle related processes. Drosophila S2 cells were treated with dsRNA targetting Sin3A, lid and both or GFP as control under normal or oxidative stress conitions induced by treatment with paraquat. mRNA profiling of these samples were performed by deep sequencing using Illumina Hiseq2500.Three biological replicates were performed.

2016-01-09 | E-GEOD-68775 | biostudies-arrayexpress

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