ARID1A, encoding a subunit of the SWI/SNF chromatin remodeling complex, is the most mutated epigenetic regulator in human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with ARID1A mutational status remain a challenge. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated ovarian tumors. This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type, tumors. The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a direct transcriptional repression of HDAC6 by ARID1A. HDAC6 inhibition selectively promoted apoptosis of ARID1A-mutated cells. HDAC6 directly deacetylated the Lysine 120 residue of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates p53' apoptotic function by upregulating HDAC6. These results indicate that pharmacological inhibition of HDAC6 is a novel therapeutic strategy involving ARID1A-mutation Overall design: RNA-seq transcription profiling of samples with altered HDAC6 activity
ARID1A-mutated ovarian cancers depend on HDAC6 activity.
Specimen part, Cell line, Treatment, Subject
View SamplesWe performed RNAseq analysis to determine the effect of MFN1 deletion on oocyte global gene expression profile. RNAseq revealed a total of 982 genes were significantly differentially expressed (p<0.05) in Mfn1-/- oocytes compared to WT (654 up-regulated and 337 down-regulated). Pathway analysis indicated significant over-representation of elements involved in regulation of ceramide biosynthesis, death receptor signaling and adherens junction signaling. Differential expression of these genes (Bad, G2e3, Cdh17 and Myh2) was also confirmed by qRT-PCR.Our findings provide new insight into the role of MFN1 in the oocytes, and may help understand the potential mechanism of infertility and reproductive aging associated with MFN1-deficiency. Overall design: Secondary follicle-enclosed oocytes were collected from 8-week-old Mfn1-/- and WT mice (n=3 for each group) and 5 oocytes from each group were pooled for RNA sequencing analysis.
Mitofusin 1 is required for female fertility and to maintain ovarian follicular reserve.
Cell line, Subject
View SamplesIdentifying the functions of proteins, which define specific subnuclear structures and territories, is important for understanding eukaryotic nuclear dynamics. Sp100 is a prototypical protein of ND10/PML bodies and co-localizes with the proto-oncogenic protein PML and Daxx, proteins with critical roles in oncogenic transformation, interferon-mediated viral resistance and response to PML-directed cancer therapeutics. Sp100 isoforms contain PHD, Bromo and HMG domains and are highly sumoylated at ND10/PML bodies, all characteristics suggestive of a role in chromatin mediated gene regulation. However, no clear role for the Sp100 component of PML bodies in oncogenesis has been defined. Using isoform-specific knockdown techniques, we show that most human diploid fibroblasts, which lack Sp100, rapidly senesce and discuss gene expression changes associated with this rapid senescence.
Sp100 as a potent tumor suppressor: accelerated senescence and rapid malignant transformation of human fibroblasts through modulation of an embryonic stem cell program.
Cell line, Treatment
View SamplesGene expression profile in CS1AN deficient and CSBwt restored cell lines after 24 hours of UV or alphe-amanitin treatment (only for restored). The comaprison of expression profile between 0 and 24 hours revealed
Regulatory interplay of Cockayne syndrome B ATPase and stress-response gene ATF3 following genotoxic stress.
Specimen part, Treatment
View SamplesThe deubiquitinase BAP1 is a candidate tumor suppressor regulating cell proliferation in human and is required for development in Drosophila. BAP1 is assembled into high molecular weight transcriptional multi-protein complexes.
The ubiquitin carboxyl hydrolase BAP1 forms a ternary complex with YY1 and HCF-1 and is a critical regulator of gene expression.
Cell line, Treatment
View SamplesThis SuperSeries is composed of the SubSeries listed below.
MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer.
Specimen part, Treatment
View SamplesRibosome Profiling was employed to learn about Ribosome A-site occupancies in response to uL11 siRNA treatment or scrambled siRNA treatment in Cystic Fibrosis Bronchial Epithelial (CFBE) cells. Overall design: Ribosome Profiling of cells 96h after siRNA transfection
Slowing ribosome velocity restores folding and function of mutant CFTR.
Specimen part, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Human but not mouse adipogenesis is critically dependent on LMO3.
Specimen part, Treatment
View SamplesIn this study we aimed to gain further insight on the role of GCs in adipocyte differentiation. For the future drugability of candidate targets it is of utmost importance to find factors relevant to human biology. Thus, we analyzed the transcriptome of GC induced primary human adipose stem cells (hASC) to identify novel factors downstream of GC action
Human but not mouse adipogenesis is critically dependent on LMO3.
Specimen part
View SamplesIn this study, we aimed to gain further insight on the role of glucocorticoids (GCs) in adipocyte differentiation. For the future drugability of candidate targets, it is of utmost importance to find factors relevant to human biology. Thus, we analyzed the transcriptome of GC-induced primary human adipose stem cells (hASCs) isolated from paired subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) to identify novel factors downstream of GC action.
Human but not mouse adipogenesis is critically dependent on LMO3.
Specimen part, Treatment
View Samples