Identification of ZDHHC14 as a novel human tumour suppressor gene

Genomic changes affecting tumour suppressor genes are fundamental to cancer. We applied SNP array analysis to a panel of testicular germ cell tumours to search for novel tumour suppressor genes and identified a frequent small deletion on 6q25.3 affecting just one gene, ZDHHC14. The expression of ZDH...

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Published in:	The Journal of pathology Vol. 232; no. 5; pp. 566 - 577
Main Authors:	Yeste-Velasco, Marc, Mao, Xueying, Grose, Richard, Kudahetti, Sakunthala C, Lin, Dongmei, Marzec, Jacek, Vasiljević, Natasa, Chaplin, Tracy, Xue, Liyan, Xu, Maojia, Foster, Julie M, Karnam, Santi S, James, Sharon Y, Chioni, Athina-Myrto, Gould, David, Lorincz, Attila T, Oliver, R Tim D, Chelala, Claude, Thomas, Gareth M, Shipley, Janet M, Mather, Stephen J, Berney, Daniel M, Young, Bryan D, Lu, Yong-Jie
Format:	Journal Article
Language:	English
Published:	Chichester, UK John Wiley & Sons, Ltd 01-04-2014 Wiley Subscription Services, Inc
Subjects:	Acyltransferases - genetics Acyltransferases - metabolism Animals Apoptosis Cell Line, Tumor Cell Proliferation Cell Survival Down-Regulation Gene Deletion Gene Expression Profiling - methods Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Genes, Tumor Suppressor HEK293 Cells Humans Male Mice Mice, Nude Neoplasms, Germ Cell and Embryonal - enzymology Neoplasms, Germ Cell and Embryonal - genetics Neoplasms, Germ Cell and Embryonal - pathology Oligonucleotide Array Sequence Analysis Polymorphism, Single Nucleotide prostate cancer Prostatic Neoplasms - enzymology Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology Prostatic Neoplasms - prevention & control RNA Interference testicular germ cell tumours Testicular Neoplasms - enzymology Testicular Neoplasms - genetics Testicular Neoplasms - pathology Time Factors Transfection Tumor Burden tumour suppressor gene ZDHHC14 tumour suppressor gene testicular germ cell tumours apoptosis prostate cancer ZDHHC14
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Summary:	Genomic changes affecting tumour suppressor genes are fundamental to cancer. We applied SNP array analysis to a panel of testicular germ cell tumours to search for novel tumour suppressor genes and identified a frequent small deletion on 6q25.3 affecting just one gene, ZDHHC14. The expression of ZDHHC14, a putative protein palmitoyltransferase with unknown cellular function, was decreased at both RNA and protein levels in testicular germ cell tumours. ZDHHC14 expression was also significantly decreased in a panel of prostate cancer samples and cell lines. In addition to our findings of genetic and protein expression changes in clinical samples, inducible overexpression of ZDHHC14 led to reduced cell viability and increased apoptosis through the classic caspase‐dependent apoptotic pathway and heterozygous knockout of ZDHHC14 decreased cell colony formation ability. Finally, we confirmed our in vitro findings of the tumour suppressor role of ZDHHC14 in a mouse xenograft model, showing that overexpression of ZDHHC14 inhibits tumourigenesis. Thus, we have identified a novel tumour suppressor gene that is commonly down‐regulated in testicular germ cell tumours and prostate cancer, as well as given insight into the cellular functional role of ZDHHC14, a potential protein palmitoyltransferase that may play a key protective role in cancer. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Bibliography:	ArticleID:PATH4327 Appendix S1. Supporting InformationTable S1. List of primers used to amplify ZDHHC14 genomic locus for next-generation sequencing.Table S2. DNA pools used for the generation of next-generation sequencing libraries.Table S3. Next-generation sequencing coverage, depth, and Phred-score of the DNA samples.Table S4. List of primer sets used to amplify the bisulphite-converted DNA and perform pyrosequencing for DNA methylation analysis.Figure S1. Affymetrix 10 K SNP array results of all unpaired TGCT samples and three cell lines.Figure S2. ZDHHC14 antibody specificity.Figure S3. Next-generation sequencing coverage and depth of the DNA samples.Figure S4. ZDHHC14 down-regulation in prostate cancer is not caused by promoter hypermethylation.Figure S5. DHHC domain is involved in apoptosis induction.Figure S6. ZDHHC14 is a highly stable protein. istex:4C568414ADFF9F6CE9D44D5A1881C151873CD684 ark:/67375/WNG-N34VVMZ3-M ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0022-3417 1096-9896
DOI:	10.1002/path.4327