CDK8 Kinase Activity Promotes Glycolysis

Abstract

SUMMARY Aerobic glycolysis, also known as the Warburg effect, is a hallmark of cancerous tissues. Despite its importance in cancer development, our understanding of mechanisms driving this form of metabolic reprogramming is incomplete. We report here an analysis of colorectal cancer cells engineered to carry a single point mutation in the active site of the Mediator-associated kinase CDK8, creating hypomorphic alleles sensitive to bulky ATP analogs. Transcriptome analysis revealed CDK8 kinase activity is required for expression of many components of the glycolytic cascade. CDK8 inhibition impairs glucose transporter expression, glucose uptake, glycolytic capacity and reserve, as well as cell proliferation and anchorage independent growth, both in normoxia and hypoxia. Importantly, CDK8 impairment sensitizes cells to pharmacological glycolysis inhibition, a result reproduced with Senexin A, a dual inhibitor of CDK8/CDK19. Altogether, these results contribute to our understanding of CDK8 as an oncogene and justify investigations to target CDK8 in highly glycolytic tumors.

The Compatibility of Alisma and Atractylodes Affects the Biological Behaviors of VSMCs Via Inhibiting miR-128-5p / p21 Gene

“…As negative regulator of cyclins, p27 and p21 are found to exert a central role in the cell cycle arrest [25,26]. The activity of cyclin-dependent kinases (CDKs) is strongly linked to the expression of cyclins, which can initiate DNA synthesis, promote cell cycle, play an important role in cell proliferation [27][28][29]. P21 prevents DNA replication from inhibiting cell proliferation through the control of CDK2, CDK4 and CDK6.…”

CDK8 and CDK19 kinases have non-redundant oncogenic functions in hepatocellular carcinoma

“…Second, constitutive activation of the β-catenin pathway in the BMEL cells did not rescue CDK8 deficiency (Supplemental Figure 2C), indicating that tumor-promoting activity of CDK8 in the liver does not rely on the activation of the β-catenin pathway, which is consistent with the lack of β-catenin-related phenotype in CDK8 Δhep livers ( Figure 2). Third, CDK8 has been proposed as a regulator of glycolysis (33), and we therefore tested whether CDK8 removal affects the metabolism of BMEL cells. However, analysis of glycolysis (Seahorse Glycolysis stress test) and mitochondrial respiration (Seahorse Mito stress test) did not reveal any effect of CDK8 ablation (Supplemental Figure 3), indicating that this regulation is not present in hepatic progenitor cells and that it does not account for the failure of CDK8-mutant cells to grow in soft agar.…”

Winning the War on Cancer

“…The Warburg effect and consequent addiction to glucose is a hallmark of cancerous tissues, something that distinguishes cancer cell from most normal tissues. Therefore, combining drugs that block CDK8 activity with those that block glycolysis may enable specific targeting of cancer cells without harmful effects on normal cells [5].…”