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Background <p>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. While cyclin-dependent kinase 9 (CDK9) is recognized as a crucial transcriptional regulator in cancer progression, its specific role in HCC pathogenesis remains poorly understood.</p> Objective <p>This study aims to investigate the specific role and underlying mechanisms of cyclin-dependent kinase 9 (CDK9) in the pathogenesis and progression of hepatocellular carcinoma (HCC).</p> Methods <p>CDK9 expression in HCC was analyzed through public databases and validated by immunohistochemistry (IHC) of clinical specimens. Compound 45 (CDK9 inhibitor) was used to assess CDK9’s functional impact. Mechanistic studies employed RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP), immunoblotting, RT-qPCR, flow cytometry, and colony formation assays. Antitumor efficacy was evaluated in xenograft models.</p> Results <p>Our study demonstrates significant CDK9 overexpression in HCC clinical samples, as confirmed through the cBioPortal for Cancer Genomics database analysis and IHC validation, with elevated expression correlating strongly with poor patient prognosis. Importantly, we reveal that pharmacological inhibition of CDK9 using Compound 45 potently induces apoptosis in HCC cells through a novel molecular mechanism. Mechanistic investigations show that CDK9 inhibition promotes c-Jun-mediated transcriptional activation of MT2A, leading to subsequent downregulation of the anti-apoptotic proteins BCL-2 and BCL-XL. Genetic ablation experiments confirm the essential role of MT2A in mediating this apoptotic pathway. Furthermore, in vivo studies using an HCC xenograft model demonstrate the significant tumor-suppressive effects of Compound 45 treatment.</p> Conclusion <p>These findings collectively identify the CDK9/c-Jun/MT2A/BCL-2/BCL-XL axis as a critical therapeutic pathway in HCC, establishing CDK9 inhibition as a promising strategy for HCC treatment.</p>

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CDK9 inhibition triggers MT2A-dependent apoptosis in HCC cells

  • 期刊论文

  • 发表日期：

    2026年4月9日

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  • Bilu Peng,
  • Yuli Bao,
  • Ziren Zhang,
  • Jianxin Lyu,
  • Linyong Du,
  • Lei Zhang,
  • Weifeng Ma

摘要

Background

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. While cyclin-dependent kinase 9 (CDK9) is recognized as a crucial transcriptional regulator in cancer progression, its specific role in HCC pathogenesis remains poorly understood.

Objective

This study aims to investigate the specific role and underlying mechanisms of cyclin-dependent kinase 9 (CDK9) in the pathogenesis and progression of hepatocellular carcinoma (HCC).

Methods

CDK9 expression in HCC was analyzed through public databases and validated by immunohistochemistry (IHC) of clinical specimens. Compound 45 (CDK9 inhibitor) was used to assess CDK9’s functional impact. Mechanistic studies employed RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP), immunoblotting, RT-qPCR, flow cytometry, and colony formation assays. Antitumor efficacy was evaluated in xenograft models.

Results

Our study demonstrates significant CDK9 overexpression in HCC clinical samples, as confirmed through the cBioPortal for Cancer Genomics database analysis and IHC validation, with elevated expression correlating strongly with poor patient prognosis. Importantly, we reveal that pharmacological inhibition of CDK9 using Compound 45 potently induces apoptosis in HCC cells through a novel molecular mechanism. Mechanistic investigations show that CDK9 inhibition promotes c-Jun-mediated transcriptional activation of MT2A, leading to subsequent downregulation of the anti-apoptotic proteins BCL-2 and BCL-XL. Genetic ablation experiments confirm the essential role of MT2A in mediating this apoptotic pathway. Furthermore, in vivo studies using an HCC xenograft model demonstrate the significant tumor-suppressive effects of Compound 45 treatment.

Conclusion

These findings collectively identify the CDK9/c-Jun/MT2A/BCL-2/BCL-XL axis as a critical therapeutic pathway in HCC, establishing CDK9 inhibition as a promising strategy for HCC treatment.