Oncotarget

Research Papers:

Inactivation of SDH and FH cause loss of 5hmC and increased H3K9me3 in paraganglioma/pheochromocytoma and smooth muscle tumors

Attje S. Hoekstra, Marieke A. de Graaff, Inge H. Briaire-de Bruijn, Cor Ras, Reza Maleki Seifar, Ivonne van Minderhout, Cees J. Cornelisse, Pancras C.W. Hogendoorn, Martijn H. Breuning, Johnny Suijker, Esther Korpershoek, Henricus P.M. Kunst, Norma Frizzell, Peter Devilee, Jean-Pierre Bayley and Judith V.M.G. Bovée _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2015; 6:38777-38788. https://doi.org/10.18632/oncotarget.6091

Metrics: PDF 3290 views  |   HTML 4462 views  |   ?  


Abstract

Attje S. Hoekstra1, Marieke A. de Graaff2, Inge H. Briaire-de Bruijn2, Cor Ras3, Reza Maleki Seifar3, Ivonne van Minderhout4, Cees J. Cornelisse2, Pancras C.W. Hogendoorn2, Martijn H. Breuning4, Johnny Suijker2, Esther Korpershoek5, Henricus P.M. Kunst6, Norma Frizzell7, Peter Devilee1,2, Jean-Pierre Bayley1 and Judith V.M.G. Bovée2

1 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

2 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

3 Department of Biotechnology, Delft University of Technology, Delft, The Netherlands

4 Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands

5 Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands

6 Department of Otorhinolaryngology, Head and Neck Surgery, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

7 Department of Pharmacology, Physiology & Neuroscience, School of Medicine, University of South Carolina, Columbia, SC, USA

Correspondence to:

Judith V.M.G. Bovée, email:

Keywords: paraganglioma, succinate dehydrogenase, fumarate hydratase, hereditary leiomyomatosis and renal cell carcinoma, methylation

Received: June 08, 2015 Accepted: September 26, 2015 Published: October 12, 2015

Abstract

Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tricarboxylic acid (TCA) cycle enzymes and tumor suppressors. Loss-of-function mutations give rise to hereditary paragangliomas/pheochromocytomas and hereditary leiomyomatosis and renal cell carcinoma. Inactivation of SDH and FH results in an abnormal accumulation of their substrates succinate and fumarate, leading to inhibition of numerous α-ketoglutarate dependent dioxygenases, including histone demethylases and the ten-eleven-translocation (TET) family of 5-methylcytosine (5mC) hydroxylases. To evaluate the distribution of DNA and histone methylation, we used immunohistochemistry to analyze the expression of 5mC, 5-hydroxymethylcytosine (5hmC), TET1, H3K4me3, H3K9me3, and H3K27me3 on tissue microarrays containing paragangliomas/pheochromocytomas (n = 134) and hereditary and sporadic smooth muscle tumors (n = 56) in comparison to their normal counterparts. Our results demonstrate distinct loss of 5hmC in tumor cells in SDH- and FH-deficient tumors. Loss of 5hmC in SDH-deficient tumors was associated with nuclear exclusion of TET1, a known regulator of 5hmC levels. Moreover, increased methylation of H3K9me3 occurred predominantly in the chief cell component of SDH mutant tumors, while no changes were seen in H3K4me3 and H3K27me3, data supported by in vitro knockdown of SDH genes. We also show for the first time that FH-deficient smooth muscle tumors exhibit increased H3K9me3 methylation compared to wildtype tumors. Our findings reveal broadly similar patterns of epigenetic deregulation in both FH- and SDH-deficient tumors, suggesting that defects in genes of the TCA cycle result in common mechanisms of inhibition of histone and DNA demethylases.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 6091