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ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65.

ABSTRACT: The NF-?B is found in almost all animal cell types and is involved in a myriad of cellular responses. Aberrant expression of NF-?B has been linked to cancer, inflammatory diseases and improper development. Little is known about transcriptional regulation of the NF-?B 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-? coactivator1? (PGC1?) to decrease transcriptional activation of the PGC1? 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.

SUBMITTER: Kim MY

PROVIDER: S-EPMC4330387 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65.

Kim Min-Young MY Koh Dong-In DI Choi Won-Il WI Jeon Bu-Nam BN Jeong Deok-yoon DY Kim Kyung-Sup KS Kim Kunhong K Kim Se-Hoon SH Hur Man-Wook MW

Nucleic acids research 20150121 3

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) ...[more]

PMID: 25609694

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Project description:BackgroundRelA/p65 a crucial member of NF-?B signaling pathway plays diverse role in mediating oncogenesis. Limited knowledge prevails on the mechanistic insights of RelA gene regulation. RNA helicase p68 apart from being a vital player of RNA metabolism acts as a transcriptional coactivator of several oncogenic transcription factors including ?-catenin and is highly implicated in cancer progression. In this study, we aim to discern the molecular mechanism of how an RNA helicase, p68 deploys a major oncogenic signaling pathway, Wnt/ ?-catenin to regulate the expression of RelA, an indispensable component of NF-?B signaling pathway towards driving colon carcinogenesis.MethodsImmunoblotting and quantitative RT-PCR was performed for determining the protein and mRNA expressions of the concerned genes respectively. Luciferase assay was employed for studying the promoter activity of RelA. Chromatin immunoprecipitation was used to evaluate the occupancy of transcription factors on the RelA promoter. Immunohistochemical analysis was conducted using FFPE sections derived from normal human colon and colon cancer patient samples. Finally, a syngeneic colorectal allograft mouse model was used to assess physiological significance of the in vitro findings.Resultsp68, ?-catenin and RelA proteins were found to bear strong positive correlation in normal and colon carcinoma patient samples. Both p68 and ?-catenin increased RelA mRNA and protein expression. p68, ?-catenin and Wnt3a elevated RelA promoter activity. Conversely, p68 and ?-catenin knockdown diminished RelA promoter activity and led to reduced RelA mRNA and protein expression. p68 was perceived to occupy RelA promoter with ?-catenin at the TCF4/LEF (TBE) sites thereby potentiating RelA transcription. p68 and ?-catenin alliance positively modulated the expression of signature NF-?B target genes. Enhanced NF-?B target gene expression by p68 was corroborated by findings in clinical samples. Tumors generated in mice colorectal allograft model, stably expressing p68 further reinforced our in vitro findings.ConclusionsWe report for the first time a novel mechanism of alliance between p68 and ?-catenin in regulating the expression of RelA and stimulating the NF-?B signaling axis towards driving colon carcinogenesis. This study unravels novel modes of p68-mediated colon carcinogenesis, marking it a potential target for therapy.

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ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65.

Publications

ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65.

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