Impact of histone methyltransferase SUV420H2 in breast cancer

Isin,Hüsniye; Özgür,Emre; Kelten Talu,Canan; Can Trabulus,Didem; Karaçetin,Didem; Gezer,Ugur

doi:10.3892/br.2020.1336

Impact of histone methyltransferase SUV420H2 in breast cancer

Authors:
- Hüsniye Isin
- Emre Özgür
- Canan Kelten Talu
- Didem Can Trabulus
- Didem Karaçetin
- Ugur Gezer
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Affiliations: Department of Basic Oncology, Oncology Institute, Istanbul University, Istanbul 34093, Turkey, Department of Pathology, Istanbul Training and Research Hospital, University of Health Sciences, Istanbul 34096, Turkey, Department of Surgery, Istanbul Training and Research Hospital, University of Health Sciences, Istanbul 34096, Turkey, Department of Radiation Oncology, Bakirkoy Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul 34147, Turkey
Published online on: July 23, 2020 https://doi.org/10.3892/br.2020.1336
Article Number: 29

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Abstract

Breast cancer is the most common type of cancer in women worldwide. Triple methylation of H4 lysine 20 (H4K20me3), a key component of epigenetic regulation of genomic integrity, is catalyzed by the methyltransferase, SUV420H2. Data on the expression status of SUV420H2 in breast cancer are limited. In the present study, the influence of SUV420H2 suppression on the proliferation of breast cancer cells was experimentally investigated. Subsequently, SUV420H2 expression was assessed in resectable breast cancer along with H4K20me3 status. SUV420H2 expression was knocked down in breast cells using small interfering RNA oligonucleotides. SUV420H2 expression was determined semi‑quantitatively at the mRNA level. H4K20me3 was measured on extracted histone proteins using an approach similar to ELISA. Suppression of the SUV420H2 gene resulted in increased cell proliferation. Although the median SUV420H2 expression values were similar in tumor tissues and non‑cancerous regions in the entire cohort (0.0022 and 0.0015, respectively; P=0.46), there was a notable difference in expression between tumor tissues and the adjacent non‑cancerous region in the majority of patients. Increased SUV420H2 expression in tumors compared with healthy tissue was predominantly observed in patients with early‑stage breast cancer, whereas reduced SUV420H2 expression was observed in tumors more frequently in patients with advanced stage diseases. There was no association between SUV420H2 expression and the tissue levels of H4K20me3. The results showed that SUV420H2 exhibited anti‑proliferative activity in vitro, and exhibits a heterogeneous expression pattern in breast cancer tissues.

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1	Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P, Ruddy K, Tsang J and Cardoso F: Breast cancer. Nat Rev Dis Primers. 5(66)2019.
2	Dogan N and Toprak D: Female breast cancer mortality rates in Turkey. Asian Pac J Cancer Prev. 15:7569–7573. 2014.
3	Torre LA, Siegel RL, Ward EM and Jemal A: Global cancer incidence and mortality rates and trends-an update. Cancer Epidemiol Biomarkers Prev. 25:16–27. 2016.PubMed/NCBI View Article : Google Scholar
4	Sauter ER: Reliable biomarkers to identify new and recurrent cancer. Eur J Breast Health. 13:162–167. 2017.PubMed/NCBI View Article : Google Scholar
5	Zhao Z and Shilatifard A: Epigenetic modifications of histones in cancer. Genome Biol. 20(245)2019. View Article : Google Scholar
6	Miller JL and Grant PA: The role of DNA methylation and histone modifications in transcriptional regulation in humans. Subcell Biochem. 61:289–317. 2013.PubMed/NCBI View Article : Google Scholar
7	Wang Y and Jia S: Degrees make all the difference: The multifunctionality of histone H4 lysine 20 methylation. Epigenetics. 4:273–276. 2009.PubMed/NCBI View Article : Google Scholar
8	Svobodová Kovaříková A, Legartová S, Krejčí J and Bártová E: H3K9me3 and H4K20me3 represent the epigenetic landscape for 53BP1 binding to DNA lesions. Aging (Albany NY). 10:2585–2605. 2018.PubMed/NCBI View Article : Google Scholar
9	Jørgensen S, Schotta G and Sørensen CS: Histone H4 lysine 20 methylation: Key player in epigenetic regulation of genomic integrity. Nucleic Acids Res. 41:2797–2806. 2013.PubMed/NCBI View Article : Google Scholar
10	Tryndyak VP, Kovalchuk O and Pogribny IP: Loss of DNA methylation and histone H4 lysine 20 trimethylation in human breast cancer cells is associated with aberrant expression of DNA methyltransferase 1, Suv4-20h2 histone methyltransferase and methyl-binding proteins. Cancer Biol Ther. 5:65–70. 2006.PubMed/NCBI View Article : Google Scholar
11	Yokoyama Y, Matsumoto A, Hieda M, Shinchi Y, Ogihara E, Hamada M, Nishioka Y, Kimura H, Yoshidome K, Tsujimoto M and Matsuura N: Loss of histone H4K20 trimethylation predicts poor prognosis in breast cancer and is associated with invasive activity. Breast Cancer Res. 16(R66)2014.PubMed/NCBI View Article : Google Scholar
12	van Nuland R and Gozani O: Histone H4 lysine 20 (H4K20) methylation, expanding the signaling potential of the proteome one methyl moiety at a time. Mol Cell Proteomics. 15:755–764. 2016.PubMed/NCBI View Article : Google Scholar
13	Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, Haydon C, Ropero S, Petrie K, et al: Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet. 37:391–400. 2005.PubMed/NCBI View Article : Google Scholar
14	Füllgrabe J, Kavanagh E and Joseph B: Histone onco-modifications. Oncogene. 30:3391–3403. 2011.PubMed/NCBI View Article : Google Scholar
15	Sakabe K, Wang Z and Hart GW: Beta-N-acetylglucosamine (O-GlcNAc) is part of the histone code. Proc Natl Acad Sci USA. 107:19915–19920. 2010.PubMed/NCBI View Article : Google Scholar
16	West AC and Johnstone RW: New and emerging HDAC inhibitors for cancer treatment. J Clin Investig. 124:30–39. 2014.PubMed/NCBI View Article : Google Scholar
17	Shanmugam MK, Arfuso F, Arumugam S, Chinnathambi A, Jinsong B, Warrier S, Wang LZ, Kumar AP, Ahn KS, Sethi G and Lakshmanan M: Role of novel histone modifications in cancer. Oncotarget. 19:11414–11426. 2017.PubMed/NCBI View Article : Google Scholar
18	Noberini R, Osti D, Miccolo C, Richichi C, Lupia M, Corleone G, Hong SP, Colombo P, Pollo B, Fornasari L, et al: Extensive and systematic rewiring of histone post-translational modifications in cancer model systems. Nucleic Acids Res. 46:3817–3832. 2018.PubMed/NCBI View Article : Google Scholar
19	Simpson NE, Tryndyak VP, Beland FA and Pogribny IP: An in vitro investigation of metabolically sensitive biomarkers in breast cancer progression. Breast Cancer Res Treat. 133:959–968. 2012. View Article : Google Scholar
20	Shinchi Y, Hieda M, Nishioka Y, Matsumoto A, Yokoyama Y, Kimura H, Matsuura S and Matsuura N: SUV420H2 suppresses breast cancer cell invasion through down regulation of the SH2 domain-containing focal adhesion protein tensin-3. Exp Cell Res. 334:90–99. 2015.PubMed/NCBI View Article : Google Scholar
21	Lakhani SR, Ellis IO, Schnitt SJ, Tan PH and van de Vijver MJ (eds): WHO classification of tumours of the breast. In: WHO Classification of Tumours. Vol 4. 4th edition. IARC, Lyon. 2012.
22	Elston CW and Ellis IO: Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: Experience from a large study with long-term follow-up. Histopathology. 19:403–410. 1991.PubMed/NCBI View Article : Google Scholar
23	Singletary SE, Allred C, Ashley P, Bassett LW, Berry D, Bland KI, Borgen PI, Clark G, Edge SB, Hayes DF, et al: Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol. 20:3628–3636. 2002.PubMed/NCBI View Article : Google Scholar
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
25	Viotti M, Wilson C, McCleland M, Koeppen H, Haley B, Jhunjhunwala S, Klijn C, Modrusan Z, Arnott D, Classon M, et al: SUV420H2 is an epigenetic regulator of epithelial/mesenchymal states in pancreatic cancer. J Cell Biol. 217:763–777. 2018.PubMed/NCBI View Article : Google Scholar
26	Elsheikh SE, Green AR, Rakha EA, Powe DG, Ahmed RA, Collins HM, Soria D, Garibaldi JM, Paish CE, Ammar AA, et al: Global histone modifications in breast cancer correlate with tumor phenotypes, prognostic factors, and patient outcome. Cancer Res. 69:3802–3809. 2009.PubMed/NCBI View Article : Google Scholar