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OTUD7B Deubiquitinates LSD1 to Govern Its Binding Partner Specificity, Homeostasis, and Breast Cancer Metastasis

ABSTRACT: OTUD7B Deubiquitinates LSD1 to Govern Its Binding Partner Specificity, Homeostasis, and Breast Cancer Metastasis

PROVIDER: PRJNA723036 | ENA |

REPOSITORIES: ENA

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OTUD7B Deubiquitinates LSD1 to Govern Its Binding Partner Specificity, Homeostasis, and Breast Cancer Metastasis [RNA-seq]

Project description:Genomic amplification of OTUD7B is frequently found across human cancers. But its role in tumorigenesis is poorly understood. Lysine‐specific demethylase 1 (LSD1) is known to execute epigenetic regulation by forming corepressor complex with CoREST/histone deacetylases (HDACs). However, the molecular mechanisms by which cells maintain LSD1/CoREST complex integrity are unknown. Here, it is reported that LSD1 protein undergoes K63‐linked polyubiquitination. OTUD7B is responsible for LSD1 deubiquitination at K226/277 residues, resulting in dynamic control of LSD1 binding partner specificity and cellular homeostasis. OTUD7B deficiency increases K63‐linked ubiquitination of LSD1, which disrupts LSD1/CoREST complex formation and targets LSD1 for p62‐mediated proteolysis. Consequently, OTUD7B deficiency impairs genome‐wide LSD1 occupancy and enhances the methylation of H3K4/H3K9, therefore profoundly impacting global gene expression and abrogating breast cancer metastasis. Moreover, physiological fluctuation of OTUD7B modulates cell cycle‐dependent LSD1 oscillation, ensuring the G1/S transition. Both OTUD7B and LSD1 proteins are overpresented in high‐grade or metastatic human breast cancer, while dysregulation of either protein is associated with poor survival and metastasis. Thus, OTUD7B plays a unique partner‐switching role in maintaining the integrity of LSD1/CoREST corepressor complex, LSD1 turnover, and breast cancer metastasis.

2021-04-20 | GSE172370 | GEO

OTUD7B Deubiquitinates LSD1 to Govern Its Binding Partner Specificity, Homeostasis, and Breast Cancer Metastasis [ChIP-seq]

2021-04-20 | GSE172369 | GEO

OTUD7B Deubiquitinates LSD1 to Govern Its Binding Partner Specificity, Homeostasis, and Breast Cancer Metastasis [ChIP-seq]

Project description:OTUD7B Deubiquitinates LSD1 to Govern Its Binding Partner Specificity, Homeostasis, and Breast Cancer Metastasis [ChIP-seq]

| PRJNA723038 | ENA

OTUD7B Deubiquitinates LSD1 to Govern Its Binding Partner Specificity, Homeostasis, and Breast Cancer Metastasis [RNA-seq]

Project description:OTUD7B Deubiquitinates LSD1 to Govern Its Binding Partner Specificity, Homeostasis, and Breast Cancer Metastasis [RNA-seq]

| PRJNA723039 | ENA

OTUD7B Deubiquitinates LSD1 to Govern Its Binding Partner Specificity, Homeostasis, and Breast Cancer Metastasis.

Project description: Not available

| S-EPMC8336515 | biostudies-literature

OTUD7B Deubiquitinates LSD1 to Govern Its Binding Partner Specificity, Homeostasis, and Breast Cancer Metastasis

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-04-20 | GSE172371 | GEO

The LSD1/KDM1A neuro-specific isoform regulates neuronal differentiation through H3K9 demethylation [Affymetrix]

Project description:During brain development, histone-modifying enzymes play an important role by orchestrating transcriptional programs that regulate neuronal maturation. Lysine-Specific Demethylase 1 (LSD1, also named as KDM1A) functions as a transcriptional repressor by removing methyl groups at lysine 4 of histone H3 (H3K4). In neurons, alternative splicing can include an additional exon (exon E8a) within LSD1 transcripts, generating a LSD1+8a neuro-specific isoform. We here report that LSD1+8a isoform does not have the intrinsic ability to demethylate H3K4. LSD1+8a functions as a co-activator on its target genes by removing H3K9 repressive histone marks. We identify the supervillin protein (SVIL) as a LSD1+8a interacting partner and demonstrate that SVIL protein regulates neuronal maturation by controlling LSD1+8a mediated H3K9 demethylation. Thus, our results show that alternative splicing provides a genius mechanism by which LSD1 isoforms can acquire a dual specificity (H3K9 vs H3K4) and therefore differentially control specific gene expression patterns during brain development. In order to find some LSD1+8a regulated genes at differentiated SH-SY5Y cell lines, we infected SH-SY5Y with control or LSD1+8a shRNA, then induced differentiation with RA and BDNF, (Retinoic acid (RA) (Sigma) was added at a final concentration of 10 μM the next day after plating. After 4 days, the cells were washed three times with PBS and incubated with 50 ng/mL of Brain Derived Neural Factor (BDNF) (Millipore) in serum-free medium for 3 days), we extracted RNA from BDNF induced SH-SY5Y cells for expression analysis.Duplicates were included for Affymetrix Human transcriptome version 2 array.

2015-06-05 | E-GEOD-63097 | biostudies-arrayexpress

The LSD1/KDM1A neuro-specific isoform regulates neuronal differentiation through H3K9 demethylation [Affymetrix]

2015-06-05 | GSE63097 | GEO

The LSD1/KDM1A neuro-specific isoform regulates neuronal differentiation through H3K9 demethylation [ChIP-Seq]

2015-06-05 | GSE58258 | GEO

Chromatin profiling of the relationship between EWS/FLI, LSD1, and K27ac in multiple Ewing sarcoma cell lines

Project description:The purpose of this study was to define the genome-wide functional relationship between LSD1 and EWS/FLI in Ewing sarcoma cells. We found EWS/FLI and LSD1 co-localize throughout the genome and that EWS/FLI induces a large change in the genomic distribution of LSD1, and that this also occurs for the LSD1 interacting partner, REST.

2020-05-12 | GSE144685 | GEO

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