Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

Hypermethylation of Promoter Region of LATS1 - a CDK Interacting Protein in Oral Squamous Cell Carcinomas - a Pilot Study in India

  • Published : 2015.03.09
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Epigenetic silencing of tumor suppressor genes due to promoter hypermethylation is one of the frequent mechanisms observed in cancers. Hypermethylation of several tumor suppressor genes involved in cell cycle regulation has been reported in many types of tumors including oral squamous cell carcinomas. LATS1 (Large Tumor Suppressor, isoform 1) is a novel tumor suppressor gene that regulates cell cycle progression by forming complexes with the cyclin dependent kinase, CDK1. Promoter hypermethylation of the LATS1 gene has been observed in several carcinomas and also has been linked with prognosis. However, the methylation status of LATS1 in oral squamous cell carcinomas is not known. As oral cancer is one of the most prevalent forms of cancer in India, the present study was designed to investigate the methylation status of LATS1 promoter and associate it with histopathological findings in order to determine any associations of the genetic status with stage of differentiation. Materials and Methods: Tumor chromosomal DNA isolated from biopsy tissues of thirteen oral squamous cell carcinoma biopsy tissues were subjected to digestion with methylation sensitive HpaII enzyme followed by amplification with primers flanking CCGG motifs in promoter region of LATS1 gene. The PCR amplicons were subsequently subjected to agarose gel electrophoresis along with undigested amplification control. Results: HpaII enzyme based methylation sensitive PCR identified LATS1 promoter hypermethylation in seven out of thirteen oral squamous cell carcinoma samples. Conclusions: The identification of LATS1 promoter hypermethylation in seven oral squamous cell carcinoma samples (54%), which included one sample with epithelial dysplasia, two early invasive and one moderately differentiated lesions indicates that the hypermethylation of this gene may be one of the early event during carcinogenesis. To the best of our knowledge, this is the first study to have explored and identified positive association between LATS1 promoter hypermethylation with histopathological features in oral squamous cell carcinomas.

Keywords

References

  1. Adduri RS, Katamoni R, Pandilla R, et al (2014). TP53 Pro72 allele is enriched in oral tongue cancer and frequently mutated in esophageal cancer in India. PLoS One, 9, 114002. https://doi.org/10.1371/journal.pone.0114002
  2. 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.
  3. Aylon Y, Oren M (2011). New plays in the p53 theater. Curr Opin Genet Dev, 21, 86-92. https://doi.org/10.1016/j.gde.2010.10.002
  4. 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.
  5. Bothos J, Tuttle RL, Ottey M, Luca FC, Halazonetis TD (2005). Human LATS1 is a mitotic exit network kinase. Cancer Res, 65, 6568-75. https://doi.org/10.1158/0008-5472.CAN-05-0862
  6. Chan TA, Glockner S, Yi JM, et al (2008). Convergence of mutation and epigenetic alterations identifies common genes in cancer that predict poor prognosis. PLoS Med, 5, 823-39.
  7. Christoph F, Hinz S, Kempkensteffen C, et al (2007). A gene expression profile of tumor suppressor genes commonly methylated in bladder cancer. J Cancer Res Clin Oncol, 133, 343-9. https://doi.org/10.1007/s00432-006-0174-9
  8. Cooks T, Harris CC (2014). p53 Mutations and Inflammation-Associated Cancer Are Linked through TNF Signaling. Mol Cell, 56, 611-2. https://doi.org/10.1016/j.molcel.2014.11.018
  9. Gao SY, Li J, Qu XY, Zhu N, Ji YB (2014). Downregulation of Cdk1 and cyclinB1 expression contributes to oridonininduced cell cycle arrest at G2/M phase and growth inhibition in SGC-7901 gastric cancer cells. Asian Pac J Cancer Prev, 15, 6437-41. https://doi.org/10.7314/APJCP.2014.15.15.6437
  10. Hao Y, Chun A, Cheung K, Rashidi B, Yang X (2008). Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem, 283, 5496-509. https://doi.org/10.1074/jbc.M709037200
  11. Hisaoka M, Tanaka A and Hashimoto H (2002). Molecular alterations of h-warts/LATS1 tumor suppressor in human soft tissue sarcoma. Lab Invest, 82, 1427-35. https://doi.org/10.1097/01.LAB.0000032381.68634.CA
  12. Jiang Z, Li X, Hu J, Zhou W, Jiang Y, Li G and Lu D (2006). Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma. Neuroscience Res, 56, 450-58. https://doi.org/10.1016/j.neures.2006.09.006
  13. Kanherkar RR, Bhatia-Dey N, Makarev E, Csoka AB (2014). Cellular reprogramming for understanding and treating human disease. Front Cell Dev Biol, 12, 67.
  14. Lin H, Fang L, Lin D (2014). Association of cyclin D1 variants with head and neck cancer susceptibility: evidence from a meta-analysis. Asian Pac J Cancer Prev, 15, 5645-51. https://doi.org/10.7314/APJCP.2014.15.14.5645
  15. Liu H, Xing Y, Yang S, Tian D (2011). Remarkable difference of somatic mutation patterns between oncogenes and tumor suppressor genes. Oncol Rep, 26, 1539-46.
  16. Mak AS (2014). p53 in cell invasion, podosomes, and invadopodia. Cell Adh Migr, 8, 205-14. https://doi.org/10.4161/cam.27841
  17. McLaughlin SK, Olsen SN, Dake B, et al (2013). The RasGAP gene, RASAL2, is a tumor and metastasis suppressor. Cancer Cell, 24, 365-78. https://doi.org/10.1016/j.ccr.2013.08.004
  18. 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
  19. 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
  20. Moran A, Fernandez-Marcelo T, Carro J, et al (2012). Methylation profiling in non-small cell lung cancer: clinical implications. Int J Oncol, 40, 739-46.
  21. Peters I, Dubrowinskaja N, Abbas M, et al (2014). DNA methylation biomarkers predict progression-free and overall survival of metastatic renal cell cancer (mRCC) treated with antiangiogenic therapies. PLoS One, 9, 91440. https://doi.org/10.1371/journal.pone.0091440
  22. Rivlin N, Brosh R, Oren M, Rotter V (2011). Mutations in the p53 tumor suppressor gene: important milestones at the various steps of tumorigenesis. Genes Cancer, 2, 466-74. https://doi.org/10.1177/1947601911408889
  23. 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
  24. Takahashi Y, Miyoshi Y, Takahata C, et al (2005). Down regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologicall aggressive phenotype in human breast cancers. Cancer Res, 11, 1380-5.
  25. Vallot C, Stransky N, Bernard-Pierrot I, et al (2011). A novel epigenetic phenotype associated with the most aggressive pathways of bladder tumor progression. J Natl Cancer Inst, 103, 47-60. https://doi.org/10.1093/jnci/djq470
  26. Visser S, Yang X (2010). LATS tumor suppressor: a new governor of cellular homeostasis. Cell Cycle, 9, 3892-903. https://doi.org/10.4161/cc.9.19.13386
  27. Marcinkiewicz KM, Gudas LJ (2014). Altered histone mark deposition and DNA methylation at homeobox genes in human oral squamous cell carcinoma. J Cell Physiol, 229, 1405-16. https://doi.org/10.1002/jcp.24577
  28. Yang H, Zhong Y, Peng C, Chen JQ, Tian D (2010). Important role of indels in somatic mutations of human cancer genes. BMC Med Genet, 11, 128. https://doi.org/10.1186/1471-2350-11-128

Cited by

  1. The LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway vol.24, pp.9, 2017, https://doi.org/10.1038/cdd.2017.99
  2. Overexpression of the YAP1 oncogene in clear cell renal cell carcinoma is associated with poor outcome vol.38, pp.1, 2017, https://doi.org/10.3892/or.2017.5642