Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma.
Biochem Biophys Res Commun
; 520(3): 544-550, 2019 12 10.
Article
em En
| MEDLINE
| ID: mdl-31615655
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Glândula Tireoide
/
Quinases Ciclina-Dependentes
/
Carcinoma Anaplásico da Tireoide
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Biochem Biophys Res Commun
Ano de publicação:
2019
Tipo de documento:
Article