WWC's Lab

     One of the hallmarks of cancer cells is their altered metabolism to sustain their high proliferation rate referred to as aerobic glycolysis, or the Warburg effect. The tumor-preferred pathway involves an increased uptake of glucose, utilization of intracellular glucose to pyruvate via glycolysis, and the conversion into lactate in the presence of sufficient oxygen. Along this metabolic flux, PKM2that catalyzes the dephosphorylation of phosphoenolpyruvate (PEP) to pyruvate, is a pivotal enzyme and selectively expressed in tumors cells. Its abundance and activity determine the metabolic flow to lactate, TCA cycle or biosynthetic pathway. There are four isoforms of pyruvate kinase in mammals: tissue-specific PKL and PKR encoded by PKLR, and PKM1 and PKM2 that are mutually exclusive products of PKM. Of note, PKM2 is expressed in highly multiplying cells including embryonic, adult stem cells, and re-expressed in tumor cells, while PKM1 expression is predominantly found in heart, brain and muscle cells that demand high ATP, suggesting that cancer cells favor the expression of PKM2.

     There are two ways that PKM2 pyruvate kinase activity can be modulated: 1) by metabolites such as FBP, serine and SAICAR as activators while Phe, Cys and T3 as negative regulators; and 2) by post-translational modifications: phosphorylation of Tyr105 by growth factor signals, oxidation of Cys358 by ROS, acetylation of Lys305 and Lys433 by high glucose. In most of these cases, suppression of PKM2 pyruvate kinase activities are favored in response to oncogenic signals.

     Yet, another remarkable way of suppressing cytosolic PKM2 activity is its translocation into nucleus, where it serves as transcriptional coactivator or as a protein kinase to modulate transcriptional program. Nuclear translocation of PKM2 would stop the glycolysis flow at PEP and accumulate intermediates, which are often precursors for biosynthesis to increase biomass. Further, nuclear PKM2’s protein kinase activities are found to phosphorylate nuclear proteins H3 and Stat3. As a transcriptional activator, it induces metabolic and oncogenic genes.

     An additional way to modulate PKM2’s activity is through partnership with an oncoprotein KDM8 reported by our team. KDM8 is first known as a histone lysine demethylase with specificity toward H3K36me2. It is involved in embryogenesis, oncogenesis, and stem-cell renewal. Overexpression and amplification of KDM8 was found in a variety of tumor tissues. Knockdown of KDM8 compromised the growth of cancer cells. We have demonstrated that the PKM2-KDM8 partnership facilitates PKM2’s nuclear translocation and HIF1a-mediated transactivation activity.Our data uncover a mechanism whereby PKM2 can be regulated by factor-binding-induced translocation, paving the way to cell metabolic reprogram (Wang et al., PNAS, 2014).