Cyclin-Dependent Kinase 8, or CDK8, functions as a protein kinase within cells, regulating various internal activities. As a member of the broader cyclin-dependent kinase family, CDK8 contributes to the network of proteins that manage cellular operations. It helps coordinate processes that maintain cellular balance and respond to environmental cues.
What is CDK8 and How Does It Work?
CDK8 is a serine/threonine protein kinase, an enzyme that adds phosphate groups to other proteins, altering their activity. It exists as a core component of the Mediator complex, a large multi-protein assembly that acts as a bridge between gene-specific activators and the general transcription machinery, including RNA Polymerase II. Within this complex, CDK8, along with cyclin C (CCNC), MED12, and MED13, forms a distinct module known as the CDK8 module.
The primary function of CDK8 within the Mediator complex involves regulating gene transcription, the process by which genetic information from DNA is converted into RNA. CDK8 influences which genes are activated or suppressed by phosphorylating specific transcription factors and the C-terminal domain (CTD) of RNA Polymerase II. This phosphorylation can either promote or inhibit gene expression, acting as a molecular switch to fine-tune the cellular response to various signals. CDK8’s activity can also influence the binding of RNA Polymerase II to the Mediator complex, further impacting transcription initiation and elongation.
Beyond Transcription: CDK8’s Wider Influence
While its role in gene transcription is well-established, CDK8 also influences other cellular processes. CDK8 impacts cell cycle progression, although it does not directly drive cell division like other cyclin-dependent kinases. It participates in the p53 transcriptional program, a pathway involved in coordinating cell cycle arrest and DNA damage response.
CDK8 also plays a part in cell growth and metabolic homeostasis. Its activity can regulate the stability of proteins like MYC, a transcription factor involved in cell proliferation, by influencing its phosphorylation. CDK8 has been implicated in developmental pathways, with roles identified in processes such as meiotic gene expression and pseudohyphal growth in yeast, suggesting conserved functions in differentiation. Its ability to phosphorylate various transcription factors and chromatin-associated proteins demonstrates its diverse regulatory roles.
CDK8’s Link to Health and Disease
Dysregulation of CDK8 is linked to various human diseases, particularly cancer. CDK8 frequently exhibits amplification and overexpression in colorectal cancer, where it acts as an oncogene. High levels of CDK8 in colorectal cancer are associated with activation of the Wnt/β-catenin pathway, which drives uncontrolled cell growth and tumor development. CDK8 promotes the proliferation of colon cancer cells and has been shown to suppress metastatic growth in preclinical models by regulating genes like TIMP3.
Beyond colorectal cancer, CDK8’s involvement has been observed in the pathogenesis of other malignancies, including gastric cancer, breast cancer, prostate cancer, and melanoma. It has also been implicated in acute myeloid leukemia (AML), where its activity can impact gene expression programs associated with super-enhancers. The dual role of CDK8 in tumor development, sometimes acting as an oncogenic factor and at other times as a tumor suppressor, suggests its effects can be context-dependent. CDK8 can also promote cancer cell survival by supporting the replication stress response and reducing DNA damage.
CDK8 as a Target for New Treatments
Given its involvement in various diseases, especially cancer, CDK8 has emerged as a target for therapeutic strategies. CDK8 inhibitors aim to block its activity to halt disease progression. These small molecules are designed to selectively modulate cancer cell transcription, impacting tumor growth and potentially sensitizing cancer cells to existing therapies.
Preclinical studies have shown that CDK8/19 inhibitors can have anti-tumor activity in various solid tumors and hematological malignancies, including acute myeloid leukemia and myelodysplastic syndrome. For instance, the selective CDK8/19 inhibitor Senexin B has entered clinical trials for advanced ER-positive breast cancer, often in combination with hormone therapy. Other CDK8 inhibitors, such as RVU120 (SEL120) and TSN084, are also undergoing clinical evaluation for advanced solid tumors and hematological cancers. These efforts demonstrate the potential of targeting CDK8 to develop drugs that improve patient outcomes.