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Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma

ABSTRACT: Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma

PROVIDER: PRJNA566339 | ENA |

REPOSITORIES: ENA

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Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma [RNA-seq]

Project description:Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer, with no effective treatment available. Identification of new anti-ATC drugs represents an urgent need. In this study, we find that ATC cells are highly sensitive to THZ531, a potent inhibitor of the transcriptional cyclin-dependent kinase (CDK), CDK12. Cell-based assays demonstrate that CDK12 inhibition significantly impedes cell cycle progression, induces apoptotic cell death, and impairs colony formation in ATC cells. THZ531 causes a loss of elongating RNA polymerase II and suppresses gene expression in ATC cells. An integrative analysis of gene expression profiles and super-enhancer landscape, combining with functional assays, leads to the discovery of two new ATC cancer genes, ZC3H4 and NEMP1. Furthermore, CDK12 inhibition enhances the sensitivity of ATC cells to doxorubicin-mediated chemotherapy. Thus, these findings indicate that CDK12 is a potential therapeutic target for ATC treatment and its inhibition may help to overcome the chemoresistance in patients with ATC

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Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma [ChIP-seq]

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Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma [ChIP-seq]

Project description:Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma [ChIP-seq]

| PRJNA566340 | ENA

Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma [RNA-seq]

Project description:Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma [RNA-seq]

| PRJNA566341 | ENA

PIAS2b dsRNAi repression kills by mitotic catastrophe anaplastic thyroid and non-thyroid carcinomas, but not normal thyroid or differentiated carcinomas

Project description:The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an undifferentiated cancer with very high mortality. Double-stranded RNA–directed RNA interference (dsRNAi) targeting the PIAS2 isoform beta (PIAS2b) inhibits growth of ATC cell lines and patient primary cultures in vitro and orthotopic patient-derived xenografts (oPDX) in vivo, but not of thyroid cell lines or non-anaplastic primary thyroid cultures (differentiated carcinoma, benign lesions, or normal). PIAS2b-dsRNAi also has an anti-cancer effect on other anaplastic human cancers (pancreas, lung, and gastric). Mechanistically, PIAS2b is required for proper mitotic spindle and centrosome assembly, and it is a dosage-sensitive protein in ATC. Strikingly, PIAS2b-dsRNAi induces mitotic catastrophe at prophase. High-throughput proteomics revealed the proteasome (PSMC5) and spindle cytoskeleton as direct targets of PIAS2b SUMOylation at mitotic initiation. PIAS2b-dsRNAi is a promising therapy for ATC and other aggressive anaplastic cancers.

2024-04-08 | PXD044110 | Pride

Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma

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

2022-09-19 | GSE137698 | GEO

p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer.

Project description:Anaplastic thyroid carcinoma (ATC) has among the worst prognosis of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. BRAF and TP53 mutations co-occur in a high proportion of ATC, particularly those associated with a precursor papillary thyroid carcinoma (PTC). In order to develop an adult-onset model of BRAF-mutant anaplastic thyroid carcinoma, we generated a novel thyroid-specific CreER transgenic mouse. We utilize a Cre-regulated BrafV600E mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from papillary to anaplastic thyroid carcinoma. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis and rapid lethality. We employed small animal ultrasound imaging to monitor autochthonous tumors, and show that treatment with the selective BRAF inhibitor PLX4720 improved survival, but did not lead to tumor regression or suppress signaling through the MAPK pathway. Combination of PLX4720 and the MEK inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines, and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma. Total RNA from five murine papillary thyroid carcinoma (PTC) tumors and five murine anaplastic thyroid carcinoma (ATC) tumors was analyzed.

2014-04-02 | E-GEOD-55933 | biostudies-arrayexpress

Determination of a cell proliferation and chromosomal instability signature in anaplastic thyroid carcinoma

Project description:A comparison of profiles of normal thryoid tissue (NT), papillary thyroid carcinoma tissue (PTC) and anaplastic thyroid carcinoma tissue (ATC) was carried out to identify expression patterns specifically associated with analplastic thyroid carcinoma Keywords: Expression profile survey of normal tissue and tumor subtypes

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Normal thyrocytes vs papillary vs anaplastic thyroid carcinomas

Project description:We profiled the gene expression of 11 anaplastic thyroid carcinomas (ATC), 49 papillary thyroid carcinomas (PTC) and 45 normal thyroids (N) We hibridized a series of anaplastic thyroid carcinomas (ATC) and papillary thyroid carcinomas (PTC) onto Affymetrix U133 Plus 2.0 arrays. ATCs were obtained from different hospitals in France and Belgium. Paired RNA samples of PTCs and non-tumoral thyroid tissues were obtained from Ukraine via the Chernobyl Tissue Bank (www.chernobyltissuebank.com). Diagnoses were confirmed by the members of the International Pathology Panel of the Chernobyl Tissue Bank.

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