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Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma

Meijuan Geng1, Yiyi Yang1, Xinyi Cao1

  • 1Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.

Biochemical and Biophysical Research Communications
|October 17, 2019
PubMed

Insights

Anaplastic thyroid carcinoma (ATC) treatment is challenging. This study reveals that inhibiting cyclin-dependent kinase 12 (CDK12) with THZ531 shows promise against aggressive ATC, potentially overcoming chemoresistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Anaplastic thyroid carcinoma (ATC) is a highly aggressive cancer with limited treatment options.
  • There is an urgent need for novel therapeutic strategies and drug targets for ATC.
  • Understanding the molecular mechanisms driving ATC progression is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the therapeutic potential of inhibiting cyclin-dependent kinase 12 (CDK12) in anaplastic thyroid carcinoma (ATC).
  • To identify novel therapeutic targets and potential drug candidates for ATC treatment.
  • To explore the role of CDK12 inhibition in overcoming chemoresistance in ATC.

Main Methods:

  • Utilized cell-based assays to evaluate the effects of THZ531, a CDK12 inhibitor, on ATC cell lines.
  • Performed integrative analysis of gene expression profiles and super-enhancer landscapes.
  • Conducted functional assays to validate newly identified ATC cancer genes.

Main Results:

  • ATC cells exhibited high sensitivity to THZ531, demonstrating impaired cell cycle progression, induced apoptosis, and reduced colony formation.
  • CDK12 inhibition led to a loss of elongating RNA polymerase II and suppressed gene expression in ATC cells.
  • Identified ZC3H4 and NEMP1 as novel ATC cancer genes and found that CDK12 inhibition enhances sensitivity to doxorubicin chemotherapy.

Conclusions:

  • CDK12 is a promising therapeutic target for anaplastic thyroid carcinoma.
  • Inhibition of CDK12 with THZ531 demonstrates significant anti-ATC activity.
  • Targeting CDK12 may offer a strategy to overcome chemoresistance in ATC patients.
Keywords:
Anaplastic thyroid carcinomaCDK12ChemoresistanceSer2 phosphorylation of pol II CTDSuper enhancerTHZ531

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