Contribution of LATS1 and LATS2 promoter methylation in OSCC development

  • Mohammad Ayoub Rigi Ladiz
  • Maryam Najafi
  • Dor Mohammad Kordi-Tamandani


The aberrant DNA methylation of the tumor suppressor genes involved in DNA Damage Response (DDR) signaling and cell cycle regulation may lead to the tumorigenesis. Our purpose here is to analyze the promoter methylation and mRNA expression levels of LATS1 and LATS2 (LATS1/2) genes in OSCC. Promoter methylation status of LATS1/2 genes was evaluated in 70 OSCC paraffin-embedded tissues and 70 normal oral samples, using Methylation Specific PCR (MSP). LATS1/2 mRNA expression profiles were also investigated in 14 OSCC patients and 14 normal samples, using real-time PCR. In both candidate genes, promoter methylation assessment revealed significant relationship between cases and controls (OR = 2.24, 95 % CI = 1.40–3.54, P = 0.001; LATS1 and OR = 15.5, 95%CI = 3.64–64.76, P < 0.001; LATS2). As well as, the evaluation of mRNA expression levels showed decreased expression in OSCC tissues in compare to control tissues. (Mean ± SD 1.74 ± 0.14 in OSCC versus 2.10 ± 0.24 in controls, P < 0.001; LATS1 and Mean ± SD 1.36 ± 0.077 in OSCC versus 1.96 ± 0.096 in controls, P < 0.001; LATS2). To the best our knowledge, this is the first report regarding the down-regulation of LATS1/2 through promoter methylation in OSCC. It is suggested to explore the down-stream transcription factors of both genes for finding the molecular mechanism of this deregulation in OSCC.


OSCC LATS1 LATS2 DNA methylation Gene expression 



We kindly acknowledge to our colleagues in department of Ophthalmology, Al-Zahra Eye Hospital, Zahedan University of Medical Sciences, and in the department of Biology, University of Sistan and Baluchestan, for their technical supports.

Compliance with ethical standards

Conflicts of interest

The authors declare no conflict of interest.

Research involving human participants

All procedures performed in studies involving human participants was in accordance with the ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. Aqeilan RI (2013) Hippo signaling: to die or not to die. Cell Death Differ 20:1287–1288CrossRefPubMedPubMedCentralGoogle Scholar
  2. Aylon Y, Michael D, Shmueli A, Yabuta N, Nojima H, Oren M (2006) A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization. Genes Dev 20:2687–2700CrossRefPubMedPubMedCentralGoogle Scholar
  3. Aylon Y, Ofir-Rosenfeld Y, Yabuta N, Lapi E, Nojima H, Lu X, Oren M (2010) The Lats2 tumor suppressor augments p53-mediated apoptosis by promoting the nuclear proapoptotic function of ASPP1. Genes Dev 24:2420–2429CrossRefPubMedPubMedCentralGoogle Scholar
  4. Chien M-H, Liu Y-F, Hsin C-H, Lin C-H, Shih C-H, Yang S-F, Cheng C-W, Lin C-W (2013) Impact of VEGF-C Gene polymorphisms and environmental factors on oral cancer susceptibility in Taiwan. PLoS One 8:e60283CrossRefPubMedPubMedCentralGoogle Scholar
  5. Choi S, Myers JN (2008) Molecular pathogenesis of oral squamous cell carcinoma: implications for therapy. J Dent Res 87:14–32CrossRefPubMedGoogle Scholar
  6. Furth N, Oren M (2011) An aurora A-Lats-aurora B axis ensures proper chromosome segregation. Cell Cycle 10:3055CrossRefPubMedGoogle Scholar
  7. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70CrossRefPubMedGoogle Scholar
  8. Jiang Z, Li X, Hu J, Zhou W, Jiang Y, Li G, Lu D (2006) Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma. Neurosci Res 56:450–458CrossRefPubMedGoogle Scholar
  9. Kordi-Tamandani DM, Moazeni-Roodi A, Rigi Ladez MA, Hashemi M, Birjandian E, Torkamanzehi A (2010a) Analysis of methylation patterns and expression profiles of p14ARF gene in patients with oral squamous cell carcinoma. Int J Biol Markers 25:99–103PubMedGoogle Scholar
  10. Kordi-Tamandani DM, Moazeni-Roodi AK, Rigi-Ladiz MA, Hashemi M, Birjandian E, Torkamanzehi A (2010b) Promoter hypermethylation and expression profile of MGMT and CDH1 genes in oral cavity cancer. Arch Oral Biol 55:809–814CrossRefPubMedGoogle Scholar
  11. Kordi-Tamandani DM, Ladies MA, Hashemi M, Moazeni-Roodi AK, Krishna S, Torkamanzehi A (2012) Analysis of p15INK4b and p16INK4a gene methylation in patients with oral squamous cell carcinoma. Biochem Genet 50:448–453CrossRefPubMedGoogle Scholar
  12. Kordi-Tamandani DM, Saberi E, Jamali S, Ladiz MA (2014) ERK and RAF1 genes: analysis of methylation and expression profiles in patients with oral squamous cell carcinoma. Br J Biomed Sci 71:100–103CrossRefPubMedGoogle Scholar
  13. Li Y, Pei J, Xia H, Ke H, Wang H, Tao W (2003) Lats2, a putative tumor suppressor, inhibits G1/S transition. Oncogene 22:4398–4405CrossRefPubMedGoogle Scholar
  14. Matallanas D, Romano D, Al-Mulla F, O'Neill E, Al-Ali W, Crespo P, Doyle B, Nixon C, Sansom O, Drosten M et al (2011) Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras. Mol Cell 44:893–906CrossRefPubMedGoogle Scholar
  15. Mikeska T, Craig JM (2014) DNA methylation biomarkers: cancer and beyond. Genes 5:821–864CrossRefPubMedPubMedCentralGoogle Scholar
  16. Najafi M, Kordi-Tamandani DM, Arish M (2016) Evaluation of LATS1 and LATS2 promoter methylation with the risk of pterygium formation. J Ophthalmol 2016:5431021CrossRefPubMedPubMedCentralGoogle Scholar
  17. Okada N, Yabuta N, Suzuki H, Aylon Y, Oren M, Nojima H (2011) A novel Chk1/2-Lats2-14-3-3 signaling pathway regulates P-body formation in response to UV damage. J Cell Sci 124:57–67CrossRefPubMedGoogle Scholar
  18. Parkin DM, Bray F, Ferlay J, Pisani P (2001) Estimating the world cancer burden: Globocan 2000. Int J Cancer 94:153–156CrossRefPubMedGoogle Scholar
  19. Perez-Sayans M, Somoza-Martin JM, Barros-Angueira F, Reboiras-Lopez MD, Gandara Rey JM, Garcia-Garcia A (2009) Genetic and molecular alterations associated with oral squamous cell cancer (review). Oncol Rep 22:1277CrossRefPubMedGoogle Scholar
  20. Piccolo S, Dupont S, Cordenonsi M (2014) The biology of YAP/TAZ: hippo signaling and beyond. Physiol Rev 94:1287–1312CrossRefPubMedGoogle Scholar
  21. Rad A, Farshchian M, Forghanifard MM, Matin MM, Bahrami AR, Geerts D (2016) A’rabi a, Memar B, Abbaszadegan MR: predicting the molecular role of MEIS1 in esophageal squamous cell carcinoma. Tumor Biol 37:1715–1725CrossRefGoogle Scholar
  22. Rigi-Ladiz MA, Kordi-Tamandani DM, Torkamanzehi A (2011) Analysis of hypermethylation and expression profiles of APC and ATM genes in patients with oral squamous cell carcinoma. Clin Epigenetics 3:6CrossRefPubMedPubMedCentralGoogle Scholar
  23. Saberi E, Kordi-Tamandani DM, Jamali S, Rigi-Ladiz MA (2014) Analysis of methylation and mRNA expression status of FADD and FAS genes in patients with oral squamous cell carcinoma. Med Oral Patol Oral Cir Bucal 19:e562–e568PubMedPubMedCentralGoogle Scholar
  24. Sadasivam S, DeCaprio JA (2013) The DREAM complex: master coordinator of cell cycle-dependent gene expression. Nat Rev Cancer 13:585–595CrossRefPubMedPubMedCentralGoogle Scholar
  25. Sasaki H, Hikosaka Y, Kawano O, Yano M, Fujii Y (2010) Hypermethylation of the large tumor suppressor genes in Japanese lung cancer. Oncol Lett 1:303–307PubMedPubMedCentralGoogle Scholar
  26. Scrace SF, O’Neill E (2012) RASSF Signalling and DNA damage: monitoring the integrity of the genome? Mol Biol Int 2012:141732CrossRefPubMedPubMedCentralGoogle Scholar
  27. Suzuki H, Yabuta N, Okada N, Torigata K, Aylon Y, Oren M, Nojima H (2013) Lats2 phosphorylates p21/CDKN1A after UV irradiation and regulates apoptosis. J Cell Sci 126:4358–4368CrossRefPubMedGoogle Scholar
  28. Takahashi Y, Miyoshi Y, Takahata C, Irahara N, Taguchi T, Tamaki Y, Noguchi S (2005) Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers. Clin Cancer Res 11:1380–1385CrossRefPubMedGoogle Scholar
  29. Tuch BB, Laborde RR, Xu X, Gu J, Chung CB, Monighetti CK, Stanley SJ, Olsen KD, Kasperbauer JL, Moore EJ et al (2010) Tumor transcriptome sequencing reveals allelic expression imbalances associated with copy number alterations. PLoS One 5:e9317CrossRefPubMedPubMedCentralGoogle Scholar
  30. Wang L, Mosel AJ, Oakley GG, Peng A (2012) Deficient DNA damage signaling leads to chemoresistance to cisplatin in oral cancer. Mol Cancer Ther 11:2401–2409CrossRefPubMedPubMedCentralGoogle Scholar
  31. Wierzbicki PM, Adrych K, Kartanowicz D, Stanislawowski M, Kowalczyk A, Godlewski J, Skwierz-Bogdanska I, Celinski K, Gach T, Kulig J et al (2013) Underexpression of LATS1 TSG in colorectal cancer is associated with promoter hypermethylation. World J Gastroenterol 19:4363–4373CrossRefPubMedPubMedCentralGoogle Scholar
  32. Xia H, Qi H, Li Y, Pei J, Barton J, Blackstad M, Xu T, Tao W (2002) LATS1 tumor suppressor regulates G2/M transition and apoptosis. Oncogene 21:1233–1241CrossRefPubMedGoogle Scholar
  33. Yabuta N, Mukai S, Okada N, Aylon Y, Nojima H (2011) The tumor suppressor Lats2 is pivotal in aurora a and aurora B signaling during mitosis. Cell Cycle 10:2724–2736CrossRefPubMedGoogle Scholar
  34. Yabuta N, Mukai S, Okamoto A, Okuzaki D, Suzuki H, Torigata K, Yoshida K, Okada N, Miura D, Ito A et al (2013) N-terminal truncation of Lats1 causes abnormal cell growth control and chromosomal instability. J Cell Sci 126:508–520CrossRefPubMedGoogle Scholar
  35. Yabuta N, Yoshida K, Mukai S, Kato Y, Torigata K, Nojima H (2016) Large tumor suppressors 1 and 2 regulate aurora-B through phosphorylation of INCENP to ensure completion of cytokinesis. Heliyon 2:e00131CrossRefPubMedPubMedCentralGoogle Scholar
  36. Zhang Q, Zhang J, Jin H, Sheng S (2013) Whole transcriptome sequencing identifies tumor-specific mutations in human oral squamous cell carcinoma. BMC Med Genet 6:28Google Scholar

Copyright information

© The International CCN Society 2016

Authors and Affiliations

  • Mohammad Ayoub Rigi Ladiz
    • 1
  • Maryam Najafi
    • 2
    • 3
  • Dor Mohammad Kordi-Tamandani
    • 3
  1. 1.Oral and dental disease research centerZahedan University of Medical ScienceZahedanIran
  2. 2.Cellular and Molecular Research CenterSabzevar University of Medical SciencesSabzevarIran
  3. 3.Departement of BiologyUniversity of Sistan and BaluchestanZahedanIran

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