DOI QR코드

DOI QR Code

BRD7 Promoter Hypermethylation as an Indicator of Well Differentiated Oral Squamous Cell Carcinomas

  • Balasubramanian, Anandh (Oral and Maxillofacial Surgery, Faculty of Dentistry, Sri Ramachandra University) ;
  • Subramaniam, Ramkumar (Oral and Maxillofacial Surgery, Faculty of Dentistry, Sri Ramachandra University) ;
  • Narayanan, Vivek (SRM Kattankulathur Dental College & Hospital) ;
  • Annamalai, Thangavelu (Rajah Muthiah Dental College and Hospital, Annamalai University) ;
  • Ramanathan, Arvind (Rajah Muthiah Dental College and Hospital, Annamalai University)
  • Published : 2015.03.09

Abstract

Background: Promoter hypermethylation mediated gene silencing of tumor suppressor genes is considered as most frequent mechanism than genetic aberrations such as mutations in the development of cancers. BRD7 is a single bromodomain containing protein that functions as a subunit of SWI/SNF chromatin-remodeling complex to regulate transcription. It also interacts with the well know tumor suppressor protein p53 to trans-activate genes involved in cell cycle arrest. Loss of expression of BRD7 has been observed in breast cancers and nasopharyngeal carcinomas due to promoter hypermethylation. However, the genetic status of BRD7 in oral squamous cell carcinomas (OSCCs) is not known, although OSCC is one of the most common among all reported cancers in the Indian population. Hence, in the present study we investigated OSCC samples to determine the occurrence of hypermethylation in the promoter region of BRD7 and understand its prevalence. Materials and Methods: Genomic DNA extracted from biopsy tissues of twenty three oral squamous cell carcinomas were digested with methylation sensitive HpaII type2 restriction enzyme that recognizes and cuts unmethylated CCGG motifs. The digested DNA samples were amplified with primers flanking the CCGG motifs in promoter region of BRD7 gene. The PCR amplified products were analyzed by agarose gel electrophoresis along with undigested amplification control. Results: Methylation sensitive enzyme technique identified methylation of BRD7 promoter region seventeen out of twenty three (74%) well differentiated oral squamous cell carcinoma samples. Conclusions: The identification of BRD7 promoter hypermethylation in 74% of well differentiated oral squamous cell carcinomas indicates that the methylation dependent silencing of BRD7 gene is a frequent event in carcinogenesis. To the best of our knowledge, the present study is the first to report the occurrence of BRD7and its high prevalence in oral squamous cell carcinomas.

Keywords

Oral carcinoma;BRD7 expression;hypermethylation;differentiation marker

References

  1. Asokan GS, Jeelani S, Gnanasundaram N (2014). Promoter hypermethylation profile of tumour suppressor genes in oral leukoplakia and oral squamous cell carcinoma. J Clin Diagn Res, 8, 9-12.
  2. Bakhtiar SM, Ali A, Barh D (2015). Epigenetics in head and neck cancer. Methods Mol Biol, 1238, 751-69. https://doi.org/10.1007/978-1-4939-1804-1_39
  3. Bhatia V, Goel MM, Makker A, et al (2014). Promoter region hypermethylation and mRNA expression of MGMT and p16 genes in tissue and blood samples of human premalignant oral lesions and oral squamous cell carcinoma. Biomed Res Int, 2014, 248419.
  4. Drost J, Mantovani F, Tocco F, et al (2010) BRD7 is a candidate tumour suppressor gene required for p53 function. Nat Cell Biol, 12, 380-9. https://doi.org/10.1038/ncb2038
  5. Ehrlich M (2009). DNA hypomethylation in cancer cells. Epigenomics, 1, 239-59. https://doi.org/10.2217/epi.09.33
  6. Gunn P, Walsh S, Roux C (2014). The nucleic acid revolution continues - will forensic biology become forensic molecular biology? Front Genet, 5, 44.
  7. Goldberg AD, Allis CD, Bernstein E (2007). Epigenetics: a landscape takes shape. Cell, 128, 635-8. https://doi.org/10.1016/j.cell.2007.02.006
  8. Hagemann S, Heil O, Lyko F, Brueckner B (2011). Azacytidine and decitabine induce gene-specific and non-random DNA demethylation in human cancer cell lines. PLoS ONE, 6, 17388. https://doi.org/10.1371/journal.pone.0017388
  9. Jiang N, Wang L, Chen J, et al (2014). Conserved and divergent patterns of DNA methylation in higher vertebrates. Genome Biol Evol, 6, 2998-3014. https://doi.org/10.1093/gbe/evu238
  10. Kanherkar RR, Bhatia-Dey N, Csoka AB (2014). Epigenetics across the human lifespan. Front Cell Dev Biol, 2, 49.
  11. Li LL, Shu XS, Wang ZH, Cao Y, Tao Q (2011). Epigenetic disruption of cell signaling in nasopharyngeal carcinoma. Chin J Cancer, 30, 231-9. https://doi.org/10.5732/cjc.011.10080
  12. Mantovani F, Drost J, Voorhoeve PM, Del Sal G, Agami R (2010). Gene regulation and tumor suppression by the bromodomain-containing protein BRD7. Cell Cycle, 9, 2777-81.
  13. Martin LJ, Wong M (2013). Aberrant regulation of DNA methylation in amyotrophic lateral sclerosis: a new target of disease mechanisms. Neurotherapeutics, 10, 722-33. https://doi.org/10.1007/s13311-013-0205-6
  14. Mehta DT, Annamalai T, Ramanathan A (2014). Lack of mutations in protein tyrosine kinase domain coding exons 19 and 21 of the EGFR gene in oral squamous cell carcinomas. Asian Pac J Cancer Prev, 15, 4623-7. https://doi.org/10.7314/APJCP.2014.15.11.4623
  15. Miao Y, Wang L, Zhang X, et al (2014). Promoter methylationmediated silencing of ${\beta}$-catenin enhances invasiveness of non-small cell lung cancer and predicts adverse prognosis. PLoS One, 9, 112258. https://doi.org/10.1371/journal.pone.0112258
  16. Mishra A, Meherotra R (2014). Head and neck cancer: global burden and regional trends in India. Asian Pac J Cancer Prev, 15, 537-50. https://doi.org/10.7314/APJCP.2014.15.2.537
  17. Park YJ, Claus R, Weichenhan D, Plass C (2011). Genomewide epigenetic modifications in cancer. Prog Drug Res, 67, 25-49.
  18. Sen N, Satija YK, Das S (2012). p53 and metabolism: old player in a new game. Transcription, 3, 119-23. https://doi.org/10.4161/trns.20094
  19. Sharan RN, Mehrotra R, Choudhury Y, Asotra K (2012). Association of betel nut with carcinogenesis: revisit with a clinical perspective. PLoS One, 7, 42759. https://doi.org/10.1371/journal.pone.0042759
  20. Sharma S, Sambyal V, Guleria K, et al (2014). TP53 polymorphisms in sporadic North Indian breast cancer patients. Asian Pac J Cancer Prev, 15, 6871-9 https://doi.org/10.7314/APJCP.2014.15.16.6871
  21. Tushar MD, Ramanathan A (2013). Tyrosine 1045 codon mutations in exon 27 of EGFR are infrequent in oral squamous cell carcinomas. Asian Pac J Cancer Prev, 14, 4279-82. https://doi.org/10.7314/APJCP.2013.14.7.4279
  22. van Vlodrop IJ, Niessen HE, Derks S, et al (2011) Analysis of promoter CpG island hypermethylation in cancer: location, location, location! Clin Cancer Res, 17, 4225-31. https://doi.org/10.1158/1078-0432.CCR-10-3394
  23. Zhou Z, Guo Y, Liu Y, et al (2014). Methylation-mediated silencing of Dlg5 facilitates bladder cancer metastasis. Exp Cell Res, 14-4827. [Epub ahead of print]

Cited by

  1. Tumor suppressor bromodomain-containing protein 7 cooperates with Smads to promote transforming growth factor-β responses vol.36, pp.3, 2017, https://doi.org/10.1038/onc.2016.204