ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65

Min Young Kim, Dong In Koh, Won Il Choi, Bu Nam Jeon, Deok Yoon Jeong, Kyung Sup Kim, Kunhong Kim, Se Hoon Kim, Man Wook Hur

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1609-1625
Number of pages17
JournalNucleic acids research
Volume43
Issue number3
DOIs
Publication statusPublished - 2015 Jan 1

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Pyruvic Acid
Genes
Glycolysis
Oxidoreductases
Glucose
Peroxisome Proliferator-Activated Receptors
Metabolic Networks and Pathways
Heterografts
Transcriptional Activation
Lactic Acid
Neoplasms
Cell Proliferation
Growth

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Kim, M. Y., Koh, D. I., Choi, W. I., Jeon, B. N., Jeong, D. Y., Kim, K. S., ... Hur, M. W. (2015). ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65. Nucleic acids research, 43(3), 1609-1625. https://doi.org/10.1093/nar/gkv026
Kim, Min Young ; Koh, Dong In ; Choi, Won Il ; Jeon, Bu Nam ; Jeong, Deok Yoon ; Kim, Kyung Sup ; Kim, Kunhong ; Kim, Se Hoon ; Hur, Man Wook. / ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65. In: Nucleic acids research. 2015 ; Vol. 43, No. 3. pp. 1609-1625.
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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.",
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Kim, MY, Koh, DI, Choi, WI, Jeon, BN, Jeong, DY, Kim, KS, Kim, K, Kim, SH & Hur, MW 2015, 'ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65', Nucleic acids research, vol. 43, no. 3, pp. 1609-1625. https://doi.org/10.1093/nar/gkv026

ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65. / Kim, Min Young; Koh, Dong In; Choi, Won Il; Jeon, Bu Nam; Jeong, Deok Yoon; Kim, Kyung Sup; Kim, Kunhong; Kim, Se Hoon; Hur, Man Wook.

In: Nucleic acids research, Vol. 43, No. 3, 01.01.2015, p. 1609-1625.

Research output: Contribution to journalArticle

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AU - Koh, Dong In

AU - Choi, Won Il

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AU - Kim, Kyung Sup

AU - Kim, Kunhong

AU - Kim, Se Hoon

AU - Hur, Man Wook

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AB - 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.

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Kim MY, Koh DI, Choi WI, Jeon BN, Jeong DY, Kim KS et al. ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65. Nucleic acids research. 2015 Jan 1;43(3):1609-1625. https://doi.org/10.1093/nar/gkv026