Related Experiment Video

Updated: Jul 15, 2025

The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia
08:55

The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia

Published on: November 30, 2016

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Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia

Bryan I Ruiz1, Xazmin H Lowman1, Ying Yang1

  • 1Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA 92697, USA.

Genes
|September 28, 2023
PubMed

Insights

Metabolic stress, specifically glutamine deprivation, increases FN14 (TNFRSF12A) expression in cancer cells. Supplementation with alpha-ketoglutarate (aKG) inhibits this increase and reduces cancer cachexia in mice.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolism

Background:

  • Tumor microenvironments often exhibit nutrient and oxygen deprivation.
  • FN14 (TNFRSF12A) inhibition in colon tumors reduces inflammation and cancer cachexia.
  • Mechanisms regulating FN14 expression under metabolic stress are largely unknown.

Purpose of the Study:

  • To investigate the link between metabolic stress and FN14 expression.
  • To explore the role of nutrient deprivation in cancer cachexia.
  • To identify molecular regulators of FN14 in response to metabolic challenges.

Main Methods:

  • Cancer cell lines were subjected to glutamine deprivation.
  • Expression levels of TNFRSF12A were analyzed.
  • Alpha-ketoglutarate (aKG) supplementation was used to assess rescue effects.
  • Histone methylation (H3K4me3) at the Tnfrsf12a promoter was examined.
  • A mouse model of cancer cachexia was employed to test in vivo efficacy of DM-aKG.

Main Results:

  • Glutamine deprivation transcriptionally induced TNFRSF12A expression in cancer cells.
  • Alpha-ketoglutarate (aKG) rescued the induction of TNFRSF12A caused by glutamine deprivation.
  • Glutamine deprivation increased H3K4me3 at the Tnfrsf12a promoter, which was reversed by DM-aKG.
  • DM-aKG inhibited Tnfrsf12a expression and cachexia-induced weight loss in a mouse model.

Conclusions:

  • Metabolic stress, specifically glutamine deprivation, upregulates FN14 (TNFRSF12A) expression via epigenetic modifications.
  • Alpha-ketoglutarate (aKG) plays a critical role in regulating FN14 expression under nutrient stress.
  • Targeting metabolic pathways with aKG may offer a therapeutic strategy for cancer cachexia.
Keywords:
FN14TNFRSF12Aalpha-ketoglutaratecachexiacancercolon cancerhistone

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