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ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65

Min-Young Kim1, Dong-In Koh1, Won-Il Choi1

  • 1Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1 Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea.

Nucleic Acids Research
|January 23, 2015
PubMed

Insights

ZBTB2 represses the RelA/p65 gene, altering glucose metabolism and promoting glycolysis. This reprogramming of metabolic pathways by ZBTB2 may drive cancer cell proliferation.

Area of Science:

  • Cellular biology
  • Molecular oncology
  • Metabolic pathways

Background:

  • Nuclear factor-kappa B (NF-κB) pathway is crucial for cellular responses, with aberrant expression linked to cancer.
  • The transcriptional regulation of NF-κB family member RelA/p65 is not well understood.
  • Sp1 transcription factor is vital for RelA/p65 gene expression.

Purpose of the Study:

  • To investigate the role of ZBTB2 in regulating RelA/p65 gene transcription.
  • To elucidate the impact of ZBTB2-mediated RelA/p65 repression on glucose metabolism and cancer progression.

Main Methods:

  • Analysis of ZBTB2's effect on Sp1 binding to the RelA/p65 promoter.
  • Assessment of PDK4 and pyruvate dehydrogenase (PDH) activity.
  • Measurement of pyruvate and lactate levels in cells with ectopic ZBTB2.
  • Evaluation of tumor growth in mouse xenografts with ZBTB2 knockdown.

Main Results:

  • ZBTB2 inhibits Sp1 binding to the RelA/p65 promoter, repressing RelA/p65 transcription.
  • Repression of RelA/p65 by ZBTB2 leads to increased PDK4 expression and PDH inhibition.
  • Cells with ectopic ZBTB2 exhibit elevated pyruvate and lactate, indicating a shift towards glycolysis.
  • Knockdown of ZBTB2 reduces tumor growth in mouse models.

Conclusions:

  • ZBTB2 promotes glycolysis over the TCA cycle by upregulating PDK4 expression via RelA/p65 repression.
  • ZBTB2 may enhance cell proliferation by reprogramming glucose metabolism, suggesting it as a potential therapeutic target in cancer.

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