Cyclin K condensates bridge CDK12 to phosphorylate and drive oncogenic YAP activation in hepatocellular carcinoma

  • Sci Adv. 2026 Jul 3;12(27):eaec6492. doi: 10.1126/sciadv.aec6492.
Yang Sun  1 ,  Yu Zhang  1 ,  Weikang Yan  2 ,  Jinlin Duan  3 ,  Ke Qiao  4 ,  Guoquan Yan  5 ,  Junyan Xue  1 ,  Jie Wang  1 ,  Ming Zhan  6 ,  Qiwei Li  2 ,  Hongcheng Wang  7 ,  Yonglong Zhang  1  7
Affiliations
  • 1. Laboratory of Targeted Therapy and Precision Medicine, Department of Clinical Laboratory, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 2. Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 3. Department of Pathology, Tongren Hospital Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 4. Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
  • 5. Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
  • 6. Department of Systems Biology, Beckman Research Institute, City of Hope, Monrovia, CA 91016, USA.
  • 7. Department of General Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
PMID: 42397909 DOI: 10.1126/sciadv.aec6492
Abstract

Targeting transcriptional condensates is an emerging paradigm for Cancer therapy. A key player is the transcriptional coactivator YAP (Yes-associated protein), which drives tumor-specific programs that fuel tumor progression and therapeutic resistance. Cyclin K, partnered with cyclin-dependent kinases (CDKs) CDK12/CDK13, is essential for transcription elongation, but its role in specific oncogenic programs was unclear. Here, we identify Cyclin K as an essential vulnerability across multiple Cancer types. The CDK12/Cyclin K complex binds YAP via Cyclin K and forms a regulatory condensate to bridge YAP phosphorylation by CDK12. Such a phosphorylation at threonine-398 impedes YAP inhibition by its canonical LATS kinases, stabilizes YAP, and enables its further condensation with TEAD4 to stimulate YAP oncogenic activity. Coexpression of CDK12/Cyclin K and YAP predicts sensitivity to Cyclin K inhibitors in hepatocellular carcinoma cells and patient-derived xenografts. Thus, we define CDK12/Cyclin K as a critical regulator of YAP-driven transcriptional addiction and a biomarker for patient stratification who mostly benefit from therapies targeting the CDK12/Cyclin K-YAP axis.

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