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  2. Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma

Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma

  • Biochem Biophys Res Commun. 2019 Dec 10;520(3):544-550. doi: 10.1016/j.bbrc.2019.10.052.
Meijuan Geng 1 Yiyi Yang 1 Xinyi Cao 1 Lin Dang 1 Tianye Zhang 1 Lirong Zhang 2
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
  • 2 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China. Electronic address: lzhang@tmu.edu.cn.
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.

Keywords

Anaplastic thyroid carcinoma; CDK12; Chemoresistance; Ser2 phosphorylation of pol II CTD; Super enhancer; THZ531.

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