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Inhibition of CDK7-dependent transcriptional addiction is a potential therapeutic target in synovial sarcoma

Xiaoyang Li1, Dylan C Dean2, Jin Yuan3

  • 1Department of Orthopedics, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China; Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
|April 3, 2022
PubMed

Insights

Cyclin-dependent kinase 7 (CDK7) is overexpressed in synovial sarcoma, driving tumor growth and progression. Inhibiting CDK7 shows promise as a novel therapeutic strategy for this aggressive cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Synovial sarcoma is an aggressive malignancy with limited treatment options.
  • Cyclin-dependent kinases (CDKs) are implicated in cancer, with CDK7 playing a role in transcription.
  • The specific role of CDK7 in synovial sarcoma pathogenesis is not well understood.

Purpose of the Study:

  • To investigate the expression and function of CDK7 in synovial sarcoma transcription.
  • To evaluate the prognostic and therapeutic potential of targeting CDK7 in synovial sarcoma.

Main Methods:

  • Analysis of CDK7 expression in synovial sarcoma cell lines and patient data.
  • Inhibition of CDK7 using siRNA and the specific inhibitor BS-181.
  • Assessment of cell viability, colony formation, apoptosis, and migration.
  • Western blot analysis to examine RNA polymerase II phosphorylation.

Main Results:

  • CDK7 overexpression correlates with advanced clinical stage, higher grade, and poorer prognosis.
  • CDK7 inhibition (siRNA or BS-181) induced dose-dependent cytotoxicity and reduced colony formation.
  • CDK7 inhibition decreased RNA polymerase II phosphorylation, pausing transcription and promoting apoptosis.
  • Targeting CDK7 reduced 3D spheroid formation and migration in synovial sarcoma cells.

Conclusions:

  • CDK7-dependent transcriptional addiction is crucial in human synovial sarcoma.
  • CDK7-specific inhibitors represent promising therapeutic agents for synovial sarcoma treatment.
Keywords:
CDK7RNA Polymerase IISelective inhibitorSynovial sarcomaTranscription cycle

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