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The TGF-β/HDAC7 axis suppresses TCA cycle metabolism in renal cancer

Hyeyoung Nam1, Anirban Kundu1, Suman Karki1

  • 1Department of Urology and.

JCI Insight
|October 5, 2021
PubMed

Insights

Renal cell carcinoma (RCC) shows suppressed TCA cycle enzymes, linked to PGC-1α loss. Reactivating PGC-1α or inhibiting TGF-β/HDAC7 restores enzyme levels and combats tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Research

Background:

  • Mitochondrial metabolism is altered in renal cell carcinoma (RCC), but TCA cycle regulation is unclear.
  • TCA cycle enzyme expression is reduced in RCC, more so than in other cancers.
  • Reduced TCA cycle enzyme expression correlates with decreased PGC-1α, a key metabolic regulator.

Purpose of the Study:

  • To investigate the mechanisms regulating the TCA cycle in RCC.
  • To explore the role of PGC-1α in TCA cycle enzyme expression in RCC.
  • To identify molecular pathways involved in TCA cycle suppression in RCC.

Main Methods:

  • Proteomic analysis of RCC tissues to quantify TCA cycle enzyme expression.
  • Assessing the correlation between TCA cycle enzymes and PGC-1α expression.
  • Re-expressing PGC-1α in RCC cells to observe effects on TCA cycle enzymes and metabolism.
  • Investigating the role of TGF-β signaling and HDAC7 in regulating TCA cycle enzymes.
  • Utilizing pharmacologic inhibition of TGF-β in an RCC orthotopic model.

Main Results:

  • Loss of TCA cycle enzyme expression is evident in RCC metastatic tissues.
  • Reduced TCA cycle enzyme expression is significantly more pronounced in RCC compared to other tumor types.
  • PGC-1α re-expression in RCC cells restored TCA cycle enzyme expression and enhanced glucose metabolism.
  • TGF-β signaling, with HDAC7, was found to suppress TCA cycle enzyme expression.
  • Pharmacologic inhibition of TGF-β restored TCA cycle enzyme expression and suppressed tumor growth in vivo.

Conclusions:

  • The TGF-β/HDAC7 axis plays a significant role in the global suppression of TCA cycle enzymes in RCC.
  • Altered mitochondrial metabolism in RCC is linked to the suppression of TCA cycle enzymes.
  • Targeting the TGF-β/HDAC7 pathway presents a potential therapeutic strategy for RCC.
Keywords:
CancerCell BiologyMitochondriaMolecular biology

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