Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial–mesenchymal transition

Abstract

Pyruvate kinase M2 (PKM2) is an alternatively spliced variant of the pyruvate kinase gene that is preferentially expressed during embryonic development and in cancer cells. PKM2 alters the final rate-limiting step of glycolysis, resulting in the cancer-specific Warburg effect (also referred to as aerobic glycolysis). Although previous reports suggest that PKM2 functions in nonmetabolic transcriptional regulation, its significance in cancer biology remains elusive. Here we report that stimulation of epithelial-mesenchymal transition (EMT) results in the nuclear translocation of PKM2 in colon cancer cells, which is pivotal in promoting EMT. Immunoprecipitation and LC-electrospray ionized TOF MS analyses revealed that EMT stimulation causes direct interaction of PKM2 in the nucleus with TGF-β-induced factor homeobox 2 (TGIF2), a transcriptional cofactor repressor of TGF-β signaling. The binding of PKM2 with TGIF2 recruits histone deacetylase 3 to the E-cadherin promoter sequence, with subsequent deacetylation of histone H3 and suppression of E-cadherin transcription. This previously unidentified finding of the molecular interaction of PKM2 in the nucleus sheds light on the significance of PKM2 expression in cancer cells.pyruvate kinase M2 | epithelial-mesenchymal transition | colorectal cancer | invasion | transforming growth factor-β-induced factor homeobox 2 C olorectal cancer (CRC) is the second most common cancer in the world, with more than 1.2 million new cases and about 600,000 deaths annually (1). Cancerous cells exploit a cancerspecific glycolytic system known as the Warburg effect (also referred to as aerobic glycolysis), which involves rapid glucose uptake and preferential conversion to lactate, despite an abundance of oxygen (2, 3). The precise mechanism underpinning aerobic glycolysis was unclear for a long time. However, in 2008, pyruvate kinase M2 (PKM2) gained attention when its expression was shown to be required for the maintenance of aerobic glycolysis (4). PKM2 is an alternatively spliced variant of the PKM gene that regulates the final rate-limiting step of glycolysis. PKM2 is expressed during embryonic development, but it is generally not expressed in most adult tissues. However, its counterpart, PKM1, is exclusively expressed in adult tissues. PKM2 has been shown to be reactivated in tumor development (5, 6). In cancer cells, PKM2 expression allows the diversion of glycolytic flux into the pentose phosphate pathway associated with attenuated pyruvate kinase activity, thereby meeting the biosynthetic demands for rapid proliferation (3).Investigations about the nuclear function of PKM2 arose after elucidation of the PKM2 metabolic function. It was identified that in cancer cells, PKM2 can translocate into the nucleus and function as a transcriptional cofactor in response to several extracellular signals, including EGF and hypoxia, subsequently activating CYCLIN D1, C-MYC, or hypoxia-inducible factor 1α (HIF-1α) (7,8). Particularly in the hypoxic condition, PKM2 interacts with HIF-1α and partici...

Overexpression of pyruvate kinase M2 associates with aggressive clinicopathological features and unfavorable prognosis in oral squamous cell carcinoma

“…22,23 Moreover, very recently, PKM2 has been identified as a key mediator of epithelial-mesenchymal transition via inhibiting E-cadherin and critical for cancer cells to acquire invasive potential. 24 Thus, our data suggest that PKM2 might serve as a pivotal oncogenic driver with multiple roles during OSCC development. Further studies are warranted to further indepth understand the detailed functions and relevant mechanisms regarding PKM2 underlying oral carcinogenesis.…”

Identification of microRNA-487b as a negative regulator of liver metastasis by regulation of KRAS in colorectal cancer

“…Western blot analysis was performed as described previously (22). Briefly, cells were collected and lysed in RIPA buffer, containing phosphatase inhibitor and protease inhibitor cocktail.…”

Cross-Talk between Alternatively Spliced UGT1A Isoforms and Colon Cancer Cell Metabolism

“…PKM2 may also be involved in other functions in tumorigenesis and metastasis, since PKM2 was shown to act in the nucleus by regulating gene expression Yang et al, 2012). However, reported to modulate migration and epithelial-mesenchymal transition (Hamabe et al, 2014;Rouleau et al, 2014;Yang et al, 2014). Consistently, levels of phospho-PKM2…”