ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65

Abstract

The NF-κB is found in almost all animal cell types and is involved in a myriad of cellular responses. Aberrant expression of NF-κB has been linked to cancer, inflammatory diseases and improper development. Little is known about transcriptional regulation of the NF-κB family member gene RelA/p65. Sp1 plays a key role in the expression of the RelA/p65 gene. ZBTB2 represses transcription of the gene by inhibiting Sp1 binding to a Sp1-binding GC-box in the RelA/p65 proximal promoter (bp, −31 to −21). Moreover, recent studies revealed that RelA/p65 directly binds to the peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α) to decrease transcriptional activation of the PGC1α target gene PDK4, whose gene product inhibits pyruvate dehydrogenase (PDH), a key regulator of TCA cycle flux. Accordingly, we observed that RelA/p65 repression by ZBTB2 indirectly results in increased PDK4 expression, which inhibits PDH. Consequently, in cells with ectopic ZBTB2, the concentrations of pyruvate and lactate were higher than those in normal cells, indicating changes in glucose metabolism flux favoring glycolysis over the TCA cycle. Knockdown of ZBTB2 in mouse xenografts decreased tumor growth. ZBTB2 may increase cell proliferation by reprogramming glucose metabolic pathways to favor glycolysis by upregulating PDK4 expression via repression of RelA/p65 expression.

Arsenic silences hepatic PDK4 expression through activation of histone H3K9 methylatransferase G9a

“…Despite conflicting evidence defining the role of PDK4 in tumorigenesis, either promoting (2, 33) or repressing carcinogenesis (3, 4); it is certain that PDK4 is an important factor to be considered in tumorigenesis. Hepatic PDK4 expression is regulated by insulin, fatty acids and hormone receptors (34–36).…”

“…The PDK4 gene encodes for the PDK4 protein within the mitochondria and has recently been linked to tumor proliferation due to its function in glucose metabolic pathways (2). Several types of cancers exhibited low expression of PDK4.…”

ZBTB 2 reads unmethylated CpG island promoters and regulates embryonic stem cell differentiation

“…However, these genes are all among the subset of genes whose expression goes up rather than down in the Zbtb2 KO, raising the question through which exact mechanisms ZBTB2 regulates gene expression. Previous studies have identified interactions between ZBTB2 and co‐activator or co‐repressor complexes containing histone acetyltransferase or deacetyltransferase activity, respectively, leading to gene activation or gene repression . In addition, ZBTB2 has been reported to interact with numerous other proteins, such as OCT4 and PTIP .…”

Krüppel-like factor 14, a coronary artery disease associated transcription factor, inhibits endothelial inflammation via NF-κB signaling pathway

“…Although the regulation of p65 nuclear translocation has been extensively studied, the transcriptional regulation of p65 is poorly understood 32 . p65 transcription is known to be activated by Sp1 33 and repressed by zinc finger and BTB domain containing 2 (ZBTB2) 34 . Our study found that KLF14 inhibited NF-κB reporter luciferase and this effect was abolished by IκBα phosphorylation inhibitors, indicating that the inhibition took place upstreaming of p65 nuclear translocation.…”