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Downregulation of OGDHL expression is associated with promoter hypermethylation in colorectal cancer

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Abstract

Cell metabolic reprogramming is one of the cancer hallmarks. Glycolysis activation, along with suppression of oxidative phosphorylation and, to a lower extent, the TCA cycle, occurs in the majority of malignant tumors. A bioinformatics search for the glucose metabolism genes that are differentially expressed in colorectal cancer (CC) was performed using the data of The Cancer Genome Atlas (TCGA) Project. OGDHL for an oxoglutarate dehydrogenase complex subunit, which is involved in the TCA cycle and is indirectly responsible for the induction of apoptosis, was identified as one of the most promising candidates. A quantitative PCR analysis showed, on average, an eightfold downregulation of OGDHL in 50% (15/30) of CC samples. Based on the TCGA data, promoter hypermethylation was assumed to be a major mechanism of OGDHL inactivation. Bisulfite sequencing identified the OGDHL promoter region (+327…+767 relative to the transcription start site) that is often methylated in CC samples with downregulated ODGHL expression (80%, 8/10) and is possibly crucial for gene inactivation. Thus, frequent and significant OGDHL downregulation due to hypermethylation of a specific promoter region was demonstrated for CC. The OGDHL promoter methylation pattern was assumed to provide a marker for differential diagnosis of CIMP+ (CpG island methylator phenotype) tumors, which display dense hypermethylation of the promoter region in many genes.

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Authors and Affiliations

  1. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia

    M. S. Fedorova, A. V. Kudryavtseva, V. A. Lakunina, A. V. Snezhkina, A. F. Sadritdinova, N. V. Melnikova, A. A. Belova, A. A. Dmitriev & G. S. Krasnov

  2. Herzen Moscow Cancer Research Institute, Ministry of Health of the Russian Federation, Moscow, 125284, Russia

    A. V. Kudryavtseva, N. N. Volchenko, E. N. Slavnova, T. V. Danilova, A. F. Sadritdinova, D. V. Sidorov, B. Ya. Alekseev, A. D. Kaprin & A. A. Dmitriev

  3. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 119991, Russia

    K. M. Klimina

  4. Orekhovich Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, 119121, Russia

    G. S. Krasnov

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  1. M. S. Fedorova
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  2. A. V. Kudryavtseva
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Correspondence to G. S. Krasnov.

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The authors equally contributed to this work.

Original Russian Text © M.S. Fedorova, A.V. Kudryavtseva, V.A. Lakunina, A.V. Snezhkina, N.N. Volchenko, E.N. Slavnova, T.V. Danilova, A.F. Sadritdinova, N.V. Melnikova, A.A. Belova, K.M. Klimina, D.V. Sidorov, B.Ya. Alekseev, A.D. Kaprin, A.A. Dmitriev, G.S. Krasnov, 2015, published in Molekulyarnaya Biologiya, 2015, Vol. 49, No. 4, pp. 678–688.

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Fedorova, M.S., Kudryavtseva, A.V., Lakunina, V.A. et al. Downregulation of OGDHL expression is associated with promoter hypermethylation in colorectal cancer. Mol Biol 49, 608–617 (2015). https://doi.org/10.1134/S0026893315040044

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