Skip to main content
SpringerLink
Log in

Functional Hypermethylation of ALDH1L1, PLCL2, and PPP2R3A in Colon Cancer

  • GENOMICS. TRANSCRIPTOMICS
  • Published:
Molecular Biology Aims and scope Submit manuscript

Abstract

DNA hypermethylation and mutations are key mechanisms for the downregulation of tumor suppressor genes. NotI-microarrays allowed us to detect hypermethylation and/or deletions in 180 NotI sites associated with 188 genes of human chromosome 3, in 24 paired (tumor/normal) colon samples. The most frequent aberrations (in more than 20% of tumor samples) were detected in the promoter regions of 20 genes. Expression and promoter methylation of these genes were analyzed using the data for paired colon samples from The Cancer Genome Atlas project. Three genes—ALDH1L1, PLCL2, and PPP2R3A—revealed a more than two-fold average decrease in expression and a negative correlation between mRNA level and promoter hypermethylation. The expression of these three genes was then evaluated in 30 paired colon samples by quantitative PCR. Frequent (in more than 60% of cases) and significant (5–9-fold on average) mRNA level decrease was found for each of the genes in the tumor samples. The results indicate a suppressor role of the ALDH1L1, PLCL2, and PPP2R3A genes in colon cancer, as well as functional significance of hypermethylation in the downregulation of these genes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.

Similar content being viewed by others

REFERENCES

  1. Kuipers E.J., Grady W.M., Lieberman D., Seufferlein T., Sung J.J., Boelens P.G., van de Velde C.J., Watanabe T. 2015. Colorectal cancer. Nat. Rev. Dis. Primers. 1, 15065.

    Article  Google Scholar 

  2. The Cancer Genome Atlas Network. 2012. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 487, 330‒337.

  3. Vogelstein B., Papadopoulos N., Velculescu V.E., Zhou S., Diaz L.A., Jr., Kinzler K.W. 2013. Cancer genome landscapes. Science. 339, 1546‒1558.

    Article  CAS  Google Scholar 

  4. Alexander J., Watanabe T., Wu T.T., Rashid A., Li S., Hamilton S.R. 2001. Histopathological identification of colon cancer with microsatellite instability. Am. J. Pathol. 158, 527‒535.

    Article  CAS  Google Scholar 

  5. Fearon E.R. 2011. Molecular genetics of colorectal cancer. Annu. Rev. Pathol. 6, 479‒507.

    Article  CAS  Google Scholar 

  6. Kudryavtseva A.V., Lipatova A.V., Zaretsky A.R., Moskalev A.A., Fedorova M.S., Rasskazova A.S., Shibukhova G.A., Snezhkina A.V., Kaprin A.D., Alekseev B.Y., Dmitriev A.A., Krasnov G.S. 2016. Important molecular genetic markers of colorectal cancer. Oncotarget. 7, 53959‒53983.

    PubMed  PubMed Central  Google Scholar 

  7. Webber C., Gospodarowicz M., Sobin L.H., Wittekind C., Greene F.L., Mason M.D., Compton C., Brierley J., Groome P.A. 2014. Improving the TNM classification: Findings from a 10-year continuous literature review. Int. J. Cancer. 135, 371‒378.

    Article  CAS  Google Scholar 

  8. Li J., Protopopov A., Wang F., Senchenko V., Petushkov V., Vorontsova O., Petrenko L., Zabarovska V., Muravenko O., Braga E., Kisselev L., Lerman M.I., Kashuba V., Klein G., Ernberg I., et al. 2002. NotI subtraction and NotI-specific microarrays to detect copy number and methylation changes in whole genomes. Proc. Natl. Acad. Sci. U. S. A.99, 10724‒10729.

    Article  CAS  Google Scholar 

  9. Dmitriev A.A., Kashuba V.I., Haraldson K., Senchenko V.N., Pavlova T.V., Kudryavtseva A.V., Anedchenko E.A., Krasnov G.S., Pronina I.V., Logi-nov V.I., Kondratieva T.T., Kazubskaya T.P., Braga E.A., Yenamandra S.P., Ignatjev I., et al. 2012. Genetic and epigenetic analysis of non-small cell lung cancer with NotI-microarrays. Epigenetics. 7, 502‒513.

    Article  CAS  Google Scholar 

  10. Krasnov G.S., Kudryavtseva A.V., Snezhkina A.V., Lakunina V.A., Beniaminov A.D., Melnikova N.V., Dmitriev A.A. 2019. Pan-cancer analysis of TCGA data revealed promising reference genes for qPCR normalization. Front. Genet. 10, 97.

    Article  CAS  Google Scholar 

  11. Krasnov G.S., Oparina N.Yu., Dmitriev A.A., Kudryavtseva A.V., Anedchenko E.A., Kondrat’eva T.T., Zabarovskii E.R., Senchenko V.N. 2011. RPN1, a new reference gene for quantitative data normalization in lung and kidney cancer. Mol. Biol. (Moscow). 45 (2), 211‒220.

    Article  CAS  Google Scholar 

  12. Melnikova N.V., Dmitriev A.A., Belenikin M.S., Koroban N.V., Speranskaya A.S., Krinitsina A.A., Krasnov G.S., Lakunina V.A., Snezhkina A.V., Sadritdinova A.F., Kishlyan N.V., Rozhmina T.A., Klimina K.M., Amosova A.V., Zelenin A.V., et al. 2016. Identification, expression analysis, and target prediction of flax genotroph microRNAs under normal and nutrient stress conditions. Front. Plant Sci. 7, 399.

    Article  Google Scholar 

  13. Senchenko V.N., Kisseljova N.P., Ivanova T.A., Dmitriev A.A., Krasnov G.S., Kudryavtseva A.V., Panasenko G.V., Tsitrin E.B., Lerman M.I., Kisseljov F.L., Kashuba V.I., Zabarovsky E.R. 2013. Novel tumor suppressor candidates on chromosome 3 revealed by NotI-microarrays in cervical cancer. Epigenetics. 8, 409‒420.

    Article  CAS  Google Scholar 

  14. Haraldson K., Kashuba V.I., Dmitriev A.A., Senchenko V.N., Kudryavtseva A.V., Pavlova T.V., Braga E.A., Pronina I.V., Kondratov A.G., Rynditch A.V., Lerman M.I., Zabarovsky E.R. 2012. LRRC3B gene is frequently epigenetically inactivated in several epithelial malignancies and inhibits cell growth and replication. Biochimie. 94, 1151‒1157.

    Article  CAS  Google Scholar 

  15. Glantz S.A. 2005. Primer of Biostatistics. New York, USA: McGraw-Hill.

    Google Scholar 

  16. Krasnov G.S., Dmitriev A.A., Melnikova N.V., Zaretsky A.R., Nasedkina T.V., Zasedatelev A.S., Senchenko V.N., Kudryavtseva A.V. 2016. CrossHub: A tool for multi-way analysis of The Cancer Genome Atlas (TCGA) in the context of gene expression regulation mechanisms. Nucleic Acids Res.44, e62.

    Article  Google Scholar 

  17. Toyota M., Ahuja N., Ohe-Toyota M., Herman J.G., Baylin S.B., Issa J.P. 1999. CpG island methylator phenotype in colorectal cancer. Proc. Natl. Acad. Sci. U. S. A.96, 8681‒8686.

    Article  CAS  Google Scholar 

  18. Ghosh A., Ghosh S., Maiti G.P., Sabbir M.G., Zabarovsky E.R., Roy A., Roychoudhury S., Panda C.K. 2010. Frequent alterations of the candidate genes hMLH1, ITGA9 and RBSP3 in early dysplastic lesions of head and neck: Clinical and prognostic significance. Cancer Sci.101, 1511‒1520.

    Article  CAS  Google Scholar 

  19. Beniaminov A.D., Krasnov G.S., Dmitriev A.A., Puzanov G.A., Snopok B.A., Senchenko V.N., Kashuba V.I. 2016. Interaction of two tumor suppressors: phosphatase CTDSPL and Rb protein. Mol. Biol. (Moscow). 50 (3), 438–441.

    Article  CAS  Google Scholar 

  20. Krupenko S.A., Krupenko N.I. 2018. ALDH1L1 and ALDH1L2 folate regulatory enzymes in cancer. Adv. Exp. Med. Biol. 1032, 127‒143.

    Article  CAS  Google Scholar 

  21. Beniaminov A.D., Puzanov G.A., Krasnov G.S., Kaluzhny D.N., Kazubskaya T.P., Braga E.A., Kudryavtseva A.V., Melnikova N.V., Dmitriev A.A. 2018. Deep sequencing revealed a CpG methylation pattern associated with ALDH1L1 suppression in breast cancer. Front. Genet.9, 169.

    Article  Google Scholar 

  22. Oleinik N.V., Krupenko N.I., Krupenko S.A. 2011. Epigenetic silencing of ALDH1L1, a metabolic regulator of cellular proliferation, in cancers. Genes Cancer. 2, 130‒139.

    Article  CAS  Google Scholar 

  23. Dmitriev A.A., Rudenko E.E., Kudryavtseva A.V., Krasnov G.S., Gordiyuk V.V., Melnikova N.V., Stakhovsky E.O., Kononenko O.A., Pavlova L.S., Kondratieva T.T., Alekseev B.Y., Braga E.A., Senchenko V.N., Kashuba V.I. 2014. Epigenetic alterations of chromosome 3 revealed by NotI-microarrays in clear cell renal cell carcinoma. BioMed. Res. Internat.2014, 735292.

    Article  Google Scholar 

  24. Mazhar S., Taylor S.E., Sangodkar J., Narla G. 2019. Targeting PP2A in cancer: Combination therapies. Biochim. Biophys. Acta.Mol. Cell Res. 1866, 51‒63.

    CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS

Assessment of gene expression by the quantitative PCR was performed using the equipment of EIMB RAS “Genome” center (http://www.eimb.ru/ru1/ckp/ccu_genome_c.php).

Author information

Authors and Affiliations

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

    A. A. Dmitriev, A. D. Beniaminov, N. V. Melnikova, E. N. Pushkova & A. V. Kudryavtseva

  2. Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 03680, Kiev, Ukraine

    G. V. Gerashchenko & V. I. Kashuba

  3. MTC, Biomedicum, Karolinska Institutet, 17165, Stockholm, Sweden

    V. I. Kashuba

Authors
  1. A. A. Dmitriev
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. D. Beniaminov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. V. Melnikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. N. Pushkova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. V. Gerashchenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. V. Kudryavtseva
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. V. I. Kashuba
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. A. Dmitriev.

Ethics declarations

FUNDING

This work was financially supported by the Russian Science Foundation (grant 17-74-20064).

COMPLIANCE WITH ETHICAL STANDARDS

All procedures performed in this work comply with the ethical standards of the institutional committee for research ethics and the 1964 Helsinki Declaration and its subsequent changes, or comparable ethical standards.

Conflict of interests. The authors declare no conflict of interest.

Additional information

Translated by P. Vikhreva

Abbreviations: CC, colon cancer; CIN, chromosome instability; MSI, microsatellite instability; CIMP, CpG island methylator phenotype.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dmitriev, A.A., Beniaminov, A.D., Melnikova, N.V. et al. Functional Hypermethylation of ALDH1L1, PLCL2, and PPP2R3A in Colon Cancer. Mol Biol 54, 178–184 (2020). https://doi.org/10.1134/S0026893320010057

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0026893320010057

Keywords:

Search

Navigation