1. Academic Validation
  2. Targeting CDK12 obviates the malignant phenotypes of colorectal cancer through the Wnt/β-catenin signaling pathway

Targeting CDK12 obviates the malignant phenotypes of colorectal cancer through the Wnt/β-catenin signaling pathway

  • Exp Cell Res. 2023 Apr 24;113613. doi: 10.1016/j.yexcr.2023.113613.
Shenglan Liu 1 Junhong Wu 1 Xiaolu Lu 1 Caiyao Guo 2 Qisheng Zheng 1 Yu Wang 2 Qiao Hu 1 Shuigen Bian 3 Li Luo 3 Qilai Cheng 1 Zhiping Liu 4 Wei Dai 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Gannan Medical University, Ganzhou, 341000, China.
  • 2 School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, 341000, China.
  • 3 Department of Pharmacy, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China.
  • 4 School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, China. Electronic address: Zhiping.Liu@gmu.edu.cn.
  • 5 School of Pharmacy, Gannan Medical University, Ganzhou, 341000, China. Electronic address: daiwei@gmu.edu.cn.
Abstract

Colorectal Cancer (CRC) is the second most common cause of cancer-related mortality and lies third in terms of morbidity due to the limited number of effective druggable targets. Since Cancer Stem Cells (CSCs) are considered to be one of the roots of tumorigenesis, outgrowth and metastasis, targeting CSCs may be a promising strategy to reverse the malignant phenotypes of CRC. Cyclin-dependent kinase 12 (CDK12) has been reported to be involved in the self-renewal of CSCs in various cancers, rendering it an attractive potential target against CSCs to consequently limit the malignant phenotypes in CRC. In the present study, we aimed to investigate whether CDK12 can be a potential therapeutic target for patients with CRC and clarify its underlying mechanism. We found that CDK12, but not CDK13 is required for CRC survival. CDK12 was found to drive tumor initiation according to the colitis-associated colorectal Cancer mouse model. In addition, CDK12 promoted CRC outgrowth and hepatic metastasis in the subcutaneous allograft and liver metastasis mouse models, respectively. In particular, CDK12 was able to induce the self-renewal of CRC CSCs. Mechanistically, the activation of Wnt/β-catenin signaling mediated by CDK12 was implicated in stemness regulation and malignant phenotype maintenance. These findings indicate that CDK12 is a candidate druggable target in CRC. Therefore, the CDK12 Inhibitor SR-4835 warrants clinical trial testing in patients with CRC.

Keywords

Colorectal cancer; Cyclin-dependent kinase 12; Initiation; Metastasis; Outgrowth; Wnt/β-catenin pathway.

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