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CDK12 is a promising therapeutic target for the transcription cycle and DNA damage response in metastatic

Zihao Li1, Xiaoyang Li2, Nicole A Seebacher3,4

  • 1Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 10021China.

Carcinogenesis
|July 31, 2024
PubMed

Insights

Overexpression of cyclin-dependent kinase 12 (CDK12) is linked to poorer outcomes in osteosarcoma. Inhibiting CDK12 shows promise as a new therapeutic strategy for this bone cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Osteosarcoma (OS) is a prevalent bone cancer in young individuals, with current treatments largely unchanged for decades.
  • Novel therapeutic targets are urgently needed for osteosarcoma, and cyclin-dependent kinases (CDKs) are promising candidates.
  • The specific role and therapeutic potential of CDK12 in osteosarcoma pathogenesis are not well understood.

Purpose of the Study:

  • To investigate the expression, function, and prognostic significance of CDK12 in metastatic osteosarcoma.
  • To evaluate CDK12 as a potential therapeutic target for osteosarcoma treatment.

Main Methods:

  • Analysis of CDK12 expression in relation to tumor grade, progression, and patient survival.
  • Experimental manipulation of CDK12 levels using small interfering RNA (siRNA) and inhibition with the CDK12-targeting agent THZ531.
  • Assessment of cellular processes including transcription, DNA damage repair, cell proliferation, apoptosis, and cell mobility.

Main Results:

  • Elevated CDK12 expression correlated with higher tumor grade, advanced progression, and reduced patient survival.
  • CDK12 knockdown or inhibition via THZ531 induced significant, dose- and time-dependent cytotoxicity.
  • CDK12 downregulation disrupted transcription (RNAP II phosphorylation), impaired DNA damage repair (increased γH2AX), and inhibited cell proliferation (PI3K-AKT pathway).
  • Apoptosis was promoted, indicated by altered Bax and Bcl-xL expression.
  • THZ531 treatment inhibited 3D spheroid formation, 2D colony growth, and cell migration.

Conclusions:

  • CDK12 is clinically significant in metastatic osteosarcoma, serving as a potential prognostic biomarker.
  • Targeting CDK12 with agents like THZ531 represents a promising therapeutic strategy for osteosarcoma.
Keywords:
CDK12DNA damage and repairosteosarcomatherapeutic targettranscription cycle

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