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

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

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Although clear cell renal cell carcinoma (ccRCC) has been shown to result in widespread aberrant cytosine methylation and loss of 5-hydroxymethylcytosine (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 strongly associated with aggressive clinicopathologic features and was an independent adverse prognostic factor. Loss of 5hmC also predicted reduced progression-free survival after resection of nonmetastatic disease. The loss of 5hmC in ccRCC was not due to mutational or transcriptional inactivation of ten eleven translocation (TET) enzymes, but to their functional inactivation by l-2-hydroxyglutarate (L2HG), which was overexpressed due to the deletion and underexpression of L2HG 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.

Original languageEnglish (US)
Pages (from-to)1612-1625
Number of pages14
JournalJournal of Clinical Investigation
Volume129
Issue number4
DOIs
StatePublished - Apr 1 2019

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Renal Cell Carcinoma
Ascorbic Acid
Methylation
Cytosine
Protein Transport
Growth
5-hydroxymethylcytosine
Epigenomics
Disease-Free Survival
Fluorescence
Genome
Enzymes
Therapeutics
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Shenoy, N., Bhagat, T. D., Cheville, J., Lohse, C., Bhattacharyya, S., Tischer, A., ... Verma, A. (2019). Ascorbic acid–induced TET activation mitigates adverse hydroxymethylcytosine loss in renal cell carcinoma. Journal of Clinical Investigation, 129(4), 1612-1625. https://doi.org/10.1172/JCI98747

Ascorbic acid–induced TET activation mitigates adverse hydroxymethylcytosine loss in renal cell carcinoma. / Shenoy, Niraj; Bhagat, Tushar D.; Cheville, John; Lohse, Christine; Bhattacharyya, Sanchari; Tischer, Alexander; Machha, Venkata; Gordon-Mitchell, Shanisha; Choudhary, Gaurav; Wong, Li Fan; Gross, Lou Ann; Ressigue, Emily; Leibovich, Bradley; Boorjian, Stephen A.; Steidl, Ulrich; Wu, Xiaosheng; Pradhan, Kith; Gartrell, Benjamin; Agarwal, Beamon; Pagliaro, Lance; Suzuki, Masako; Greally, John M.; Rakheja, Dinesh; Houston Thompson, R.; Susztak, Katalin; Witzig, Thomas Elmer; Zou, Yiyu; Verma, Amit.

In: Journal of Clinical Investigation, Vol. 129, No. 4, 01.04.2019, p. 1612-1625.

Research output: Contribution to journalArticle

Shenoy, N, Bhagat, TD, Cheville, J, Lohse, C, Bhattacharyya, S, Tischer, A, Machha, V, Gordon-Mitchell, S, Choudhary, G, Wong, LF, Gross, LA, Ressigue, E, Leibovich, B, Boorjian, SA, Steidl, U, Wu, X, Pradhan, K, Gartrell, B, Agarwal, B, Pagliaro, L, Suzuki, M, Greally, JM, Rakheja, D, Houston Thompson, R, Susztak, K, Witzig, TE, Zou, Y & Verma, A 2019, 'Ascorbic acid–induced TET activation mitigates adverse hydroxymethylcytosine loss in renal cell carcinoma', Journal of Clinical Investigation, vol. 129, no. 4, pp. 1612-1625. https://doi.org/10.1172/JCI98747
Shenoy, Niraj ; Bhagat, Tushar D. ; Cheville, John ; Lohse, Christine ; Bhattacharyya, Sanchari ; Tischer, Alexander ; Machha, Venkata ; Gordon-Mitchell, Shanisha ; Choudhary, Gaurav ; Wong, Li Fan ; Gross, Lou Ann ; Ressigue, Emily ; Leibovich, Bradley ; Boorjian, Stephen A. ; Steidl, Ulrich ; Wu, Xiaosheng ; Pradhan, Kith ; Gartrell, Benjamin ; Agarwal, Beamon ; Pagliaro, Lance ; Suzuki, Masako ; Greally, John M. ; Rakheja, Dinesh ; Houston Thompson, R. ; Susztak, Katalin ; Witzig, Thomas Elmer ; Zou, Yiyu ; Verma, Amit. / Ascorbic acid–induced TET activation mitigates adverse hydroxymethylcytosine loss in renal cell carcinoma. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 4. pp. 1612-1625.
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AU - Shenoy, Niraj

AU - Bhagat, Tushar D.

AU - Cheville, John

AU - Lohse, Christine

AU - Bhattacharyya, Sanchari

AU - Tischer, Alexander

AU - Machha, Venkata

AU - Gordon-Mitchell, Shanisha

AU - Choudhary, Gaurav

AU - Wong, Li Fan

AU - Gross, Lou Ann

AU - Ressigue, Emily

AU - Leibovich, Bradley

AU - Boorjian, Stephen A.

AU - Steidl, Ulrich

AU - Wu, Xiaosheng

AU - Pradhan, Kith

AU - Gartrell, Benjamin

AU - Agarwal, Beamon

AU - Pagliaro, Lance

AU - Suzuki, Masako

AU - Greally, John M.

AU - Rakheja, Dinesh

AU - Houston Thompson, R.

AU - Susztak, Katalin

AU - Witzig, Thomas Elmer

AU - Zou, Yiyu

AU - Verma, Amit

PY - 2019/4/1

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N2 - Although clear cell renal cell carcinoma (ccRCC) has been shown to result in widespread aberrant cytosine methylation and loss of 5-hydroxymethylcytosine (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 strongly associated with aggressive clinicopathologic features and was an independent adverse prognostic factor. Loss of 5hmC also predicted reduced progression-free survival after resection of nonmetastatic disease. The loss of 5hmC in ccRCC was not due to mutational or transcriptional inactivation of ten eleven translocation (TET) enzymes, but to their functional inactivation by l-2-hydroxyglutarate (L2HG), which was overexpressed due to the deletion and underexpression of L2HG 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.

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