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Ascorbic acid-induced TET activation mitigates adverse hydroxymethylcytosine loss in renal cell carcinoma

Niraj Shenoy1, Tushar D Bhagat1, John Cheville2

  • 1Albert Einstein College of Medicine, Montefiore Medical Center, New York, New York, USA.

The Journal of Clinical Investigation
|February 1, 2019
PubMed

Insights

Loss of 5-hydroxymethylcytosine (5hmC) in clear cell renal cell carcinoma (ccRCC) correlates with poor prognosis and aggressive disease. Ascorbic acid (AA) shows promise in restoring 5hmC levels and inhibiting ccRCC growth.

Area of Science:

  • Epigenetics
  • Oncology
  • Molecular Biology

Background:

  • Clear cell renal cell carcinoma (ccRCC) exhibits aberrant DNA methylation and reduced 5-hydroxymethylcytosine (5hmC) levels.
  • The prognostic significance and therapeutic potential of these epigenetic alterations remain underexplored.

Purpose of the Study:

  • To investigate the prognostic impact of 5hmC loss in ccRCC.
  • To elucidate the mechanisms underlying 5hmC loss in ccRCC.
  • To evaluate the therapeutic potential of ascorbic acid (AA) in ccRCC.

Main Methods:

  • Analysis of 576 primary ccRCC samples to correlate 5hmC levels with clinicopathologic features and survival.
  • Investigated the role of TET enzymes and L-2-hydroxyglutarate (L2HG) in 5hmC regulation.
  • Assessed the effect of ascorbic acid (AA) on ccRCC cell growth in vitro and in vivo, and on intratumoral 5hmC levels.

Main Results:

  • Loss of 5hmC was significantly associated with aggressive ccRCC features and predicted adverse outcomes, including reduced progression-free survival.
  • 5hmC loss was attributed to functional inactivation of TET enzymes by overexpressed L2HG, resulting from L2HGDH deletion/underexpression, not TET mutations.
  • Ascorbic acid (AA) restored genome-wide 5hmC levels by activating TET enzymes and inhibited ccRCC growth in vitro and in vivo, with increased intratumoral 5hmC.

Conclusions:

  • Reduced 5hmC is an independent adverse prognostic factor in ccRCC.
  • L2HG-mediated TET enzyme inactivation is a key mechanism for 5hmC loss in ccRCC.
  • High-dose ascorbic acid (AA) demonstrates preclinical therapeutic potential for ccRCC by restoring 5hmC and inhibiting tumor growth.
Keywords:
CancerOncology

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