SREBP1 drives Keratin 80-dependent cytoskeletal changes and invasive behavior in endocrine resistant ERα breast cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA515297 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8445102_1.fastq.gz | Fastqsanger.gz | |||
| SRR8445102_2.fastq.gz | Fastqsanger.gz | |||
| SRR8445103_1.fastq.gz | Fastqsanger.gz | |||
| SRR8445103_2.fastq.gz | Fastqsanger.gz | |||
| SRR8445104_1.fastq.gz | Fastqsanger.gz |
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Project description:Approximately 30% of women diagnosed with ERα breast cancer relapse with metastatic disease following adjuvant treatment with endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain (TAD) undergoes epigenetic reprogramming in cells that develop resistance to aromatase inhibitors (AI), leading to keratin 80 (KRT80) upregulation. In agreement, an increased number of KRT80-positive cells are observed at relapse in vivo while KRT80 expression associates with poor outcome using several clinical endpoints. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion maturation and cellular stiffening, which collectively promote cancer cell invasion. Shear-wave elasticity imaging of tumors from prospectively recruited patients shows that KRT80 levels correlate with stiffer tumors in vivo. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.
2019-05-15 | GSE125128 | GEO
Project description:Approximately 30% of ERα breast cancer patients relapse with metastatic disease following adjuvant endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain undergoes epigenetic reprogramming in aromatase inhibitors (AI)-resistant cells, leading to Keratin-80 (KRT80) upregulation. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion and cellular stiffening, collectively promoting cancer cell invasion. Shearwave elasticity imaging performed on prospectively recruited patients confirms KRT80 levels correlate with stiffer tumors. Immunohistochemistry showed increased KRT80-positive cells at relapse and, using several clinical endpoints, KRT80 expression associates with poor survival. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.
| S-EPMC6509342 | biostudies-literature
Project description:Endocrine therapy resistance remains a critical problem in the treatment of estrogen receptor alpha (ERα) breast cancer. Endocrine therapies target ERα via different modes of action. Drug resistance involves drug specific remodeling of the transcriptional and regulatory landscape. Using epigenomics and transcriptomics, we demonstrate that resistance to aromatase inhibitors (AI) induces phenotypical changes through epigenetic activation of cholesterol biosynthesis (CB) and keratin 80. Epigenetic activation is stable and involves both large topological domains and punctuated activation of single enhancers and super-enhancers. Specialized cancer cells expressing high levels of keratin 80 lead invasion through the extracellular matrix. Strikingly, we demonstrate that anti-cholesterol strategies can effectively arrest breast cancer invasion. Our work identifies a robust strategy to target resistant invasive breast cancer.
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Project description:To systematically understand how the circadian clock and the nutrient-driven rhythm integrate to regulate SREBP1 activity, we evaluated genome-wide the binding of SREBP1 to its targets along the day in wild-type (WT) C57BL/6mice. The recruitment of SREBP1 to the DNA showed a highly circadian behaviour, with a maximum during the fed status. However, the temporal expression of SREBP1 targets was not always synchronized with its binding. In particular, a different phase of expression was observed for SREBP1 target genes depending on their function, suggesting the involvement of other transcription factors in their regulation. The proper temporal expression pattern of these genes was dramatically changed in Bmal1KO mice upon time-restricted feeding, in spite of the rhythmic, although slightly delayed, binding of SREBP1. Our results show that besides the nutrient-driven regulation of SREBP1 nuclear translocation, a second layer of modulation of SREBP1 transcriptional activity exists and is strongly dependent from the circadian core clock. This system allows to fine tune the expression timing of SREBP1 target genes, thus helping to temporally separate the different physiological processes in which these genes are involved. 6 samples examined, 6 SREBP1 samples, as well as 6 Polr2b and 6 input samples from GEO series GSE35788 CycliX Consortium was a contributor to this submission.
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Project description:Estrogen Receptor alpha (ERα), a nuclear receptor with transcriptional activity, is a master regulator of estrogen signaling, widely known as therapeutic target in hormone-responsive breast cancer (BC). Moreover, ERα is highly expressed in approximately 80% of High Grade Serous Ovarian Cancer (HGSOC), the most common epithelial ovarian carcinoma. Despite some promising clinical trials evaluating endocrine therapy in this type of tumor, the role of ERα is still unknown. Epigenetic changes, such as DNA methylation, are emerging as key contributing factors to carcinogenesis. Disruptor of telomeric silencing-1-like (DOT1L), the only known histone methyl transferase capable to produce H3K79 mono, di and tri-methylation, modulates ERα actions in hormone-responsive BC. Considering this evidence, ERα-DOT1L association was confirmed in ERα-positive OC cells, PEO1 and PEO4, by Co-IP. DOT1L pharmacological inhibition by EPZ004777 (EPZ) revealed the involvement of this epigenetic enzyme in cell proliferation, cell cycle progression and apoptosis. Transcriptome profiling after ICI (a Selective Estrogen Receptor Degrader) and EPZ treatment, in both cell lines, has underlined a deep impact of both compounds on ERα-modulated genes, including the down-regulation of ERα itself. On the other hand, functional analysis showed that commonly affected transcripts are involved in different cellular processes, such as cancer cell survival, chemoresistance and cell cycle progression. Moreover, ChIP-qPCR performed on ERα promoter highlighted ERα and DOT1L co-localization, both in PEO1 and in PEO4 cells, which was reduced after EPZ treatment, suggesting a role of this complex on receptor transcriptional activity. In addition, drug combination studies performed with EPZ and ICI showed an additive effect in cell growth inhibition. Taken together, these results suggest DOT1L as a potential therapeutic target in the treatment of OC.
2019-11-04 | E-MTAB-8198 | biostudies-arrayexpress
Project description:Gene expression profiling reveals a potential effect of microsphere keratin in stimulating hair growth in vivo Mice back was depilated and then treated with 1% milliQ, 1% minoxidil, 1% keratin, 1% microsphere keratin for 20 days. Then the skin was collected and RNA was extracted from thetreatd skin as explained in the following section. The microarray was conducted for two biological replicates
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Project description:To systematically understand how the circadian clock and the nutrient-driven rhythm integrate to regulate SREBP1 activity, we evaluated genome-wide the binding of SREBP1 to its targets along the day in wild-type (WT) C57BL/6mice. The recruitment of SREBP1 to the DNA showed a highly circadian behaviour, with a maximum during the fed status. However, the temporal expression of SREBP1 targets was not always synchronized with its binding. In particular, a different phase of expression was observed for SREBP1 target genes depending on their function, suggesting the involvement of other transcription factors in their regulation. The proper temporal expression pattern of these genes was dramatically changed in Bmal1KO mice upon time-restricted feeding, in spite of the rhythmic, although slightly delayed, binding of SREBP1. Our results show that besides the nutrient-driven regulation of SREBP1 nuclear translocation, a second layer of modulation of SREBP1 transcriptional activity exists and is strongly dependent from the circadian core clock. This system allows to fine tune the expression timing of SREBP1 target genes, thus helping to temporally separate the different physiological processes in which these genes are involved.
2014-03-10 | GSE48375 | GEO
Project description:We identified caspase-4/S1P/SREBP1 pathway that is activated in LPS-treated macrophages. To analyze the functions of caspase-4 and SREBP1 in gene expression in macrophages, we analyzed the effects of deletions of Casp4 and Srebf1 in bone marrow-derived macrophages by RNA-seq.
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