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Depression: 21st Century Solutions + The Dark Side of Wheat

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Abstract Title:

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

Abstract Source:

J Clin Invest. 2019 Jan 31. Epub 2019 Jan 31. PMID: 30702441

Abstract Author(s):

Niraj Shenoy, Tushar D Bhagat, John C Cheville, Christine Lohse, Sanchari Bhattacharyya, Alexander Tischer, Venkata Machha, Shanisha Gordon-Mitchell, Gaurav S Choudhary, Li-Fan Wong, LouAnn Gross, Emily Ressegue, Bradley C Leibovich, Stephen A Boorjian, Ulrich Steidl, Xiaosheng Wu, Kith Pradhan, Benjamin Gartrell, Beamon Agarwal, Lance Pagliaro, Masako Suzuki, John M Greally, Dinesh Rakheja, R Houston Thompson, Katalin Susztak, Thomas Witzig, Yiyu Zou, Amit Verma

Article Affiliation:

Niraj Shenoy

Abstract:

Although ccRCC has been shown to have widespread aberrant cytosine methylation and loss of hydroxymethylation (5hmC), the prognostic impact and therapeutic targeting of this epigenetic aberrancy has not been fully explored. Analysis of 576 primary ccRCC samples demonstrated that loss of 5hmC was significantly associated with aggressive clinicopathologic features and was an independent adverse prognostic factor. Loss of 5hmC also predicted reduced progression free survival after resection of non-metastatic disease. The loss of 5hmC in ccRCC was not due to mutational or transcriptional inactivation of TET enzymes, but by their functional inactivation by l-2-hydroxyglutarate (L2HG) that was overexpressed due to the deletion and under-expression of l-2-hydroxyglutarate dehydrogenase (L2HGDH). Ascorbic acid (AA) reduced methylation and restored genome wide 5hmC levels via TET activation. Fluorescence quenching of the recombinant TET-2 protein was unaffected by L2HG in the presence of AA. Pharmacologic AA treatment led to reduced growth of ccRCC in vitro and reduced tumor growth in vivo, with increased intratumoral 5hmC. These data demonstrate that reduced 5hmC is associated with reduced survival in ccRCC and provide a preclinical rationale for exploring the therapeutic potential of high dose AA in ccRCC.

Study Type : Animal Study, In Vitro Study

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Sayer Ji
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Depression: 21st Century Solutions + The Dark Side of Wheat

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