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A Murine Cell Line Based Model of Chronic CDK9 Inhibition to Study Widespread Non-Genetic Transcriptional Elongation Defects TEdeff in Cancers
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Inhibition of CDK9 exhibits anticancer activity in hepatocellular carcinoma cells via targeting ribonucleotide

Jiunn-Chang Lin1, Tsang-Pai Liu1, Yan-Bin Chen2

  • 1Department of Surgery, MacKay Memorial Hospital, Taipei 10449, Taiwan; MacKay Junior College of Medicine, Nursing, and Management, New Taipei City 11260, Taiwan; Department of Medicine, MacKay Medical College, New Taipei City 25245, Taiwan; Liver Medical Center, MacKay Memorial Hospital, Taipei 10449, Taiwan; PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.

Toxicology and Applied Pharmacology
|May 28, 2023
PubMed

Insights

Cyclin-dependent kinase 9 (CDK9) protein levels predict survival in hepatocellular carcinoma (HCC). CDK9 inhibitors reduce HCC growth by degrading RRM2, impacting DNA synthesis and repair.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Cyclin-dependent kinase 9 (CDK9) inhibitors represent a novel anticancer therapy class.
  • Their impact on hepatocellular carcinoma (HCC) remains underexplored.
  • Ribonucleotide reductase (RR), comprising RRM1 and RRM2 subunits, is crucial for DNA synthesis and repair.

Purpose of the Study:

  • Investigate the prognostic significance of CDK9 in HCC.
  • Elucidate the molecular mechanisms of CDK9 inhibitors in HCC treatment.
  • Determine the relationship between CDK9, RRM1/RRM2, and immune cell infiltration in HCC.

Main Methods:

  • Analysis of CDK9 protein expression in HCC patient tissues.
  • Assessment of a CDK9-selective inhibitor (LDC000067) on HCC cell lines.
  • Investigation of RRM1 and RRM2 expression and degradation pathways.
  • Correlation analysis of gene expression and immune cell infiltration.

Main Results:

  • CDK9 protein expression in non-tumor tissue predicted HCC patient survival.
  • LDC000067 inhibited HCC cell growth by downregulating RRM1 and RRM2 expression post-transcriptionally.
  • LDC000067 induced RRM2 protein degradation via proteasome, lysosome, and calcium-dependent pathways.
  • CDK9 positively correlated with RRM1/RRM2 expression, and all three were linked to increased immune cell infiltration.

Conclusions:

  • CDK9 holds prognostic relevance for HCC.
  • CDK9 inhibitors exert anticancer effects by targeting RRM1/RRM2 expression and RRM2 degradation.
  • CDK9, RRM1, and RRM2 are associated with immune microenvironment modulation in HCC.
Keywords:
Cyclin-dependent kinase 9Hepatocellular carcinomaProtein degradationRibonucleotide reductase

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