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BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

Aberrant Promoter Methylation of YAP Gene and its Subsequent Downregulation in Indian Breast Cancer Patients

Authors: Sumayya Abdul Sattar Real, Farah Parveen, Asad Ur Rehman, Mohammad Aasif Khan, Sankaravamasam Venkata Suryanarayan Deo, Nootan Kumar Shukla, Syed Akhtar Husain

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

YAP, a potent oncogene and major downstream effector of the mammalian Hippo tumor suppressor pathway can act as either oncogene or tumor suppressor gene based on the type of tissue involved. Despite various studies, the role and mechanism through which YAP mediates its tumor suppressor or oncogenic effects are not yet fully understood. Therefore in the present study we aimed to investigate YAP at DNA, mRNA and protein level and also attempted to correlate our molecular findings with various clinicopathological variables of the patients.

Methods

The study comprised of a total 137 genetically unrelated women with sporadic breast cancer cases and normal adjacent tissues not infiltrated with tumor. Mutation of YAP gene was analyzed by automated DNA sequencing. YAP promoter methylation was studied using MS-PCR. Expression at mRNA and protein level was studied using qPCR and IHC respectively.

Results

In our study YAP mRNA expression was found to be 8.65 ± 6.17 fold downregulated in 67.15% cases. The expression of YAP when analyzed at the protein level by IHC was found to be absent in 78.83% cases. Results from MS-PCR analysis showed that YAP promoter methylation plays an important role in declining the expression of YAP protein. The absence of YAP protein coincided with 86.60% methylated cases thereby showing a very strong correlation (p = 0.001). We also investigated YAP mutation at the major check point sites in the Hippo pathway and observed no mutation. A significant association was observed on correlating mRNA expression with clinical stages (p = 0.038) and protein expression with ER status (p = 0.018) among Indian breast cancer patients.

Conclusion

The expression of YAP was found to be downregulated in response to aberrant promoter methylation. The downregulation of YAP are consistent with previous studies suggesting it to have a tumor suppressive role in breast cancer. We did not observe any mutation at the major check point sites in the Hippo pathway.
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Literature
1.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.CrossRefPubMed
2.
Eroles P, Bosch A, Perez-Fidalgo JA, Lluch A. Molecular biology in breast cancer: intrinsic subtypes and signaling pathways. Cancer Treat Rev. 2012;38(6):698–707.CrossRefPubMed
3.
Shi P, Feng J, Chen C. Hippo pathway in mammary gland development and breast cancer. Acta Biochim Biophys Sin (Shanghai). 2015;47(1):53–9.CrossRefPubMed
4.
Maugeri-Sacca M, Barba M, Pizzuti L, Vici P, Di Lauro L, Dattilo R, Vitale I, Bartucci M, Mottolese M, De Maria R. The Hippo transducers TAZ and YAP in breast cancer: oncogenic activities and clinical implications. Expert Rev Mol Med. 2015;17:e14.CrossRefPubMed
5.
Kim SK, Jung WH, Koo JS. Yes-associated protein (YAP) is differentially expressed in tumor and stroma according to the molecular subtype of breast cancer. Int J Clin Exp Pathol. 2014;7(6):3224–34.PubMedPubMedCentral
6.
Sudol M, Shields DC, Farooq A. Structures of YAP protein domains reveal promising targets for development of new cancer drugs. Semin Cell Dev Biol. 2012;23(7):827–33.CrossRefPubMedPubMedCentral
7.
Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, Deng CX, Brugge JS, Haber DA. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci USA. 2006;103(33):12405–10.CrossRefPubMed
8.
Basu S, Totty NF, Irwin MS, Sudol M, Downward J. Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol Cell. 2003;11(1):11–23.CrossRefPubMed
9.
Steinhardt AA, Gayyed MF, Klein AP, Dong J, Maitra A, Pan D, Montgomery EA, Anders RA. Expression of Yes-associated protein in common solid tumors. Hum Pathol. 2008;39(11):1582–9.CrossRefPubMedPubMedCentral
10.
Tufail R, Jorda M, Zhao W, Reis I, Nawaz Z. Loss of Yes-associated protein (YAP) expression is associated with estrogen and progesterone receptors negativity in invasive breast carcinomas. Breast Cancer Res Treat. 2012;131(3):743–50.CrossRefPubMed
11.
Lamar JM, Stern P, Liu H, Schindler JW, Jiang ZG, Hynes RO. The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain. Proc Natl Acad Sci USA. 2012;109(37):E2441–50.CrossRefPubMed
12.
Wang H, Du YC, Zhou XJ, Liu H, Tang SC. The dual functions of YAP-1 to promote and inhibit cell growth in human malignancy. Cancer Metastasis Rev. 2014;33(1):173–81.CrossRefPubMed
13.
14.
15.
Baylin SB, Esteller M, Rountree MR, Bachman KE, Schuebel K, Herman JG. Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet. 2001;10(7):687–92.CrossRefPubMed
16.
Sambrook JR, Russel DW. DW 2001. In: Molecular Cloning: A Laboratory Manual; 2001.
17.
Network CGA. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.CrossRef
18.
Chin L, Andersen JN, Futreal PA. Cancer genomics: from discovery science to personalized medicine. Nat Med. 2011;17(3):297–303.CrossRefPubMed
19.
Tomczak K, Czerwinska P, Wiznerowicz M. The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol (Pozn). 2015;19(1A):A68–77.PubMedPubMedCentral
20.
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E et al: Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013; 6(269):pl1.
21.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4.CrossRefPubMed
22.
Li LC, Dahiya R. MethPrimer: designing primers for methylation PCRs. Bioinformatics. 2002;18(11):1427–31.CrossRefPubMed
23.
Greenbaum D, Colangelo C, Williams K, Gerstein M. Comparing protein abundance and mRNA expression levels on a genomic scale. Genome Biol. 2003;4(9):117.CrossRefPubMedPubMedCentral
24.
Baldi P, Long AD. A Bayesian framework for the analysis of microarray expression data: regularized t -test and statistical inferences of gene changes. Bioinformatics. 2001;17(6):509–19.CrossRefPubMed
25.
Szallasi Z. Genetic network analysis in light of massively parallel biological data acquisition. Pac Symp Biocomput. 1999:5–16.
26.
Yuan M, Tomlinson V, Lara R, Holliday D, Chelala C, Harada T, Gangeswaran R, Manson-Bishop C, Smith P, Danovi SA, et al. Yes-associated protein (YAP) functions as a tumor suppressor in breast. Cell Death Differ. 2008;15(11):1752–9.CrossRefPubMed
27.
Strano S, Munarriz E, Rossi M, Castagnoli L, Shaul Y, Sacchi A, Oren M, Sudol M, Cesareni G, Blandino G. Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J Biol Chem. 2001;276(18):15164–73.CrossRefPubMed
28.
Jaramillo-Rodriguez Y, Cerda-Flores RM, Ruiz-Ramos R, Lopez-Marquez FC, Calderon-Garciduenas AL. YAP expression in normal and neoplastic breast tissue: an immunohistochemical study. Arch Med Res. 2014;45(3):223–8.CrossRefPubMed
29.
Dhananjayan SC, Ramamoorthy S, Khan OY, Ismail A, Sun J, Slingerland J, O'Malley BW, Nawaz Z. WW domain binding protein-2, an E6-associated protein interacting protein, acts as a coactivator of estrogen and progesterone receptors. Mol Endocrinol. 2006;20(10):2343–54.CrossRefPubMed
30.
Wu L, Shen Y, Peng X, Zhang S, Wang M, Xu G, Zheng X, Wang J, Lu C. Aberrant promoter methylation of cancer-related genes in human breast cancer. Oncol Lett. 2016;12(6):5145–55.CrossRefPubMedPubMedCentral
31.
Baylin SB. DNA methylation and gene silencing in cancer. Nat Clin Pract Oncol. 2005;2(Suppl 1):S4–11.CrossRefPubMed
32.
Jiang LL, Xie JK, Cui JQ, Wei D, Yin BL, Zhang YN, Chen YH, Han X, Wang Q, Zhang CL. Promoter methylation of yes-associated protein (YAP) gene in polycystic ovary syndrome. Medicine (Baltimore). 2017;96(2):e5768.CrossRefPubMedPubMedCentral
33.
Turker MS. Gene silencing in mammalian cells and the spread of DNA methylation. Oncogene. 2002;21(35):5388–93.CrossRefPubMed
34.
Hao Y, Chun A, Cheung K, Rashidi B, Yang X. Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem. 2008;283(9):5496–509.CrossRefPubMed
35.
Oka T, Mazack V, Sudol M. Mst2 and Lats kinases regulate apoptotic function of Yes kinase-associated protein (YAP). J Biol Chem. 2008;283(41):27534–46.CrossRefPubMed
36.
Oudhoff MJ, Freeman SA, Couzens AL, Antignano F, Kuznetsova E, Min PH, Northrop JP, Lehnertz B, Barsyte-Lovejoy D, Vedadi M, Arrowsmith CH, Nishina H, Gold MR, Rossi FM, Gingras AC, Zaph C. Control of the hippo pathway by Set7-dependent methylation of Yap. Dev Cell. 2013;26(2):188–94.CrossRefPubMed
37.
Andrade D, Mehta M, Griffith J, Panneerselvam J, Srivastava A, Kim TD, Janknecht R, Herman T, Ramesh R, Munshi A. YAP1 inhibition radiosensitizes triple negative breast cancer cells by targeting the DNA damage response and cell survival pathways. Oncotarget. 2017;8(58):98495–508.CrossRefPubMedPubMedCentral
38.
39.
Zhao B, Ye X, Yu J, Li L, Li W, Li S, Lin JD, Wang CY, Chinnaiyan AM, Lai ZC, et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 2008;22(14):1962–71.CrossRefPubMedPubMedCentral
Metadata
Title
Aberrant Promoter Methylation of YAP Gene and its Subsequent Downregulation in Indian Breast Cancer Patients
Authors
Sumayya Abdul Sattar Real
Farah Parveen
Asad Ur Rehman
Mohammad Aasif Khan
Sankaravamasam Venkata Suryanarayan Deo
Nootan Kumar Shukla
Syed Akhtar Husain
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4627-8

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