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Chromatinized PKC-q directly regulates inducible genes in epithelial to mesenchymal transition and breast cancer stem cells

ABSTRACT: Epithelial to mesenchymal transition (EMT) is activated during cancer invasion and metastasis, enriches for cancer stem cells (CSCs), and contributes to therapeutic resistance and disease recurrence. Signal transduction kinases play a pivotal role as chromatin-anchored proteins in eukaryotes. Here we report for the first time that protein kinase C-theta (PKC-q) regulates EMT by acting as a critical chromatin-anchored switch for inducible genes via TGF-β and the key inflammatory regulatory protein, NFkB. Chromatinized PKC-q exists as an active transcription complex and is required to establish a permissive chromatin state at signature EMT genes. Genome-wide analysis identifies a unique cohort of inducible PKC-q-sensitive genes that are directly tethered to PKC-q in the mesenchymal state. Collectively, we show that crosstalk between signaling kinases and chromatin is critical for eliciting inducible transcriptional programs that drive mesenchymal differentiation and CSC formation, providing novel mechanisms to target using epigenetic therapy in breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE53320 | GEO | 2014/06/22

SECONDARY ACCESSION(S): PRJNA231742

REPOSITORIES: GEO

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Chromatinized PKC-q directly regulates inducible genes in epithelial to mesenchymal transition and breast cancer stem cells

Project description:Epithelial to mesenchymal transition (EMT) is activated during cancer invasion and metastasis, enriches for cancer stem cells (CSCs), and contributes to therapeutic resistance and disease recurrence. Signal transduction kinases play a pivotal role as chromatin-anchored proteins in eukaryotes. Here we report for the first time that protein kinase C-theta (PKC-q) regulates EMT by acting as a critical chromatin-anchored switch for inducible genes via TGF-M-NM-2 and the key inflammatory regulatory protein, NFkB. Chromatinized PKC-q exists as an active transcription complex and is required to establish a permissive chromatin state at signature EMT genes. Genome-wide analysis identifies a unique cohort of inducible PKC-q-sensitive genes that are directly tethered to PKC-q in the mesenchymal state. Collectively, we show that crosstalk between signaling kinases and chromatin is critical for eliciting inducible transcriptional programs that drive mesenchymal differentiation and CSC formation, providing novel mechanisms to target using epigenetic therapy in breast cancer. 2 biological samples were analysed, Immunoprecipitated and total input samples were obtained from each biological treatment. 2 Technical replicates were performed (samples from the sample lib prep were run on two different lanes).

2014-06-22 | E-GEOD-53320 | biostudies-arrayexpress

The role of PKCtheta in Epithelial to Mesenchymal Transistion

2014-06-22 | E-GEOD-53267 | biostudies-arrayexpress

The role of PKCtheta in Epithelial to Mesenchymal Transistion

2014-06-22 | GSE53267 | GEO

The role of LSD1 in Epithelial to Mesenchymal Transition

Project description:Complex regulatory networks control epithelial-to-mesenchymal transition (EMT) but the underlying epigenetic control is poorly understood. Lysine-specific demethylase 1 (LSD1) is a key histone demethylase that alters the epigenetic landscape. Here we explored the role of LSD1 in global epigenetic regulation of EMT, cancer stem cells (CSCs), the tumour microenvironment, and therapeutic resistance in breast cancer. LSD1 induced pan-genomic gene expression in networks implicated in EMT and selectively elicits gene expression programs in CSCs whilst repressing non-CSC programs. LSD1 phosphorylation at serine-111 (LSD1-s111p) by chromatin anchored protein kinase C-theta (PKC-θ), is critical for its demethylase and EMT promoting activity and LSD1-s111p is enriched in chemoresistant cells in vivo. LSD1 couples to PKC-θ on the mesenchymal gene epigenetic template promotes LSD1-mediated gene induction. In vivo, chemotherapy reduced tumour volume, and when combined with an LSD1 inhibitor, abrogated the mesenchymal signature and promoted an innate, M1 macrophage-like tumouricidal immune response. Circulating tumour cells (CTCs) from metastatic breast cancer (MBC) patients were enriched with LSD1 and pharmacological blockade of LSD1 suppressed the mesenchymal and stem-like signature in these patient-derived CTCs. Overall, LSD1 inhibition may serve as a promising epigenetic adjuvant therapy to subvert its pleiotropic roles in breast cancer progression and treatment resistance.

2018-01-11 | GSE104753 | GEO

LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer

2018-01-11 | GSE104754 | GEO

Project description:Regulation of inducible genes in epithelial to mesenchymal transition by chromatinized PKC-theta

| PRJNA231740 | ENA

Investigating the effects on the tumour and tumour environment transcriptome, of inhibiting PKC in conjunction with Docetaxel treatment [RNA-seq]

Project description:The breast tumour microenvironment (TME) includes fibroblasts, adipocytes, inflammatory and immune cells. While treatment of tumours with chemotherapeutic agents such as Docetaxel, leads to apoptosis of tumour cells, it can also have consequences for the cellular makeup and transcriptional profile of the TME and these, like increased epithelial mesenchymal transition can promote undesirable consequences, such as Cancer Stem Cell development. PKC-theta may have a role in these undesired effects. To be able to examine the effects of co-treatment of Docetaxel with an inhibitor of PKC-theta, we performed RNA-seq on tumours from mice injected with the human breast cancer cell line MDA-MB-231. We then separated reads mapped to the human and mouse genomes in silico, creating tumour and TME transcriptomes for control, Docetaxel, PKC-theta inhibitor and combination treated mice. Separation of the tumour and TME profiles illustrated a role for PKC-theta in the induction of a more basal-type transcriptome in the tumour, and of EMT in the TME.

2022-09-14 | GSE137467 | GEO

Homo sapiens

Project description:Chromatinized PKC-q directly regulates inducible genes in epithelial to mesenchymal transition and breast cancer stem cells

| PRJNA231742 | ENA

Chromatin-associated protein kinase C-0 regulates an inducible gene expression program and microRNAs in human T lymphocytes

Project description:Studies in yeast have demonstrated that signalling kinases with well known cytoplasmic functions have a surprisingly active role in the nucleus, where they are tethered to chromatin and modulate gene expression programs. Here we provide evidence for a novel function of the signal transduction kinase, protein kinase C-theta (PKC-0) that physically associates with the proximal regulatory regions of key inducible immune response genes in human T cells. Chromatin-anchored PKC-q forms hitherto undescribed nuclear complexes by interacting with active RNA polymerase II, the histone kinase MSK-1 and the adaptor molecule 14-3-3z. ChIP-on-Chip analysis reveals that PKC-0 binds directly to both the promoter and transcribed regions of genes, as well as to the promoters of microRNA genes implicated in cell migration and invasion. Moreover, enforced expression of these microRNAs is associated with heightened production of mRNAs encoding a distinct subset of inducible immune response genes. Collectively, these data suggest that in addition to its well known role as a cytoplasmic signalling kinase, PKC-0 controls immune gene expression within the nucleus of T cells by participating in chromatin-associated signalling complexes

2010-12-14 | GSE26035 | GEO

Identification of enhancers in EMT and breast cancer stem cell formation

Project description:Epithelial-mesenchymal transition (EMT), the process whereby cells gain migratory and invasive properties characteristic of mesenchymal cells, plays a central role in embryogenesis and wound healing in a wide range of tissues. However, EMT has also been linked to the formation of cancer stem cells (CSCs). Many of the signaling pathways involved in EMT have also been implicated in CSC formation but the processes that contribute uniquely to CSC formation remain elusive. We have previously demonstrated that PKCÎ¸ activation is critical for EMT induction and concomitant CSC formation in the breast cancer luminal epithelial cell line, MCF7. To discover how PKC-induced alterations in the epigenome influence the EMT and CSC formation in MCF-7 cells and MDA-MB-231, we employed a combination of expression profiling and ChIP-sequencing of H3K4me1 and H3K27ac. 3 biological samples were analyzed with two different chromatin marks.

2016-03-10 | E-GEOD-76732 | biostudies-arrayexpress

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