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Identification of ZDHHC14 as a novel tumor suppressor gene commonly downregulated in human cancers

ABSTRACT: Genomic changes affecting tumor suppressor genes (TSGs) are fundamental to cancer. We applied SNP array analysis on a panel of testicular germ cell tumors (TGCTs) to search for novel TSGs and identified a frequent small deletion on 6q25.3 containing just one gene; ZDHHC14. The expression of ZDHHC14, a putative protein palmitoyltransferase, was decreased both at RNA and protein levels in TGCTs and this decrease correlated with chemoresistance. ZDHHC14 expression was also significantly decreased in a panel of prostate cancer samples and cell lines. Through next generation sequencing of the ZDHHC14 genomic locus we discovered several mutations in both cancer types, confirming the clinical significance of our findings. Furthermore, inducible overexpression of ZDHHC14 led to reduced cell viability and increased apoptosis through the classic caspase-dependent apoptotic pathway. Finally, we confirmed our in vitro findings of the tumor suppressor role of ZDHHC14 in a mouse xenograft model, showing that overexpression of ZDHHC14 inhibits tumorigenesis. Thus we have identified a novel TSG that is commonly downregulated in human tumors, as well as given mechanistic insight into the functional role of ZDHHC14, a potential protein palmitoyltransferase about which almost nothing has been described in the literature.

ORGANISM(S): Homo sapiens

PROVIDER: GSE35216 | GEO | 2012/12/31

SECONDARY ACCESSION(S): PRJNA150645

REPOSITORIES: GEO

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Project description:Purpose: Discovery of curative therapies for renal cell carcinoma (RCC) is hampered by lack of authentic preclinical models. Tumorgrafts, generated by direct implantation of patient-derived tissues into mice, have demonstrated superior ability to predict therapeutic response. We evaluated âtissue slice graftsâ (TSGs) as an improved tumorgraft model of RCC. Experimental Design: Cores of fresh RCC were precision-cut at 300-Î¼m and implanted under the renal capsule of RAG2-/-Î³C-/- mice. Engraftment rate, histology, biomarker expression, genetic fidelity and metastatic potential were evaluated. Magnetic resonance imaging (MRI) was tested as a non-invasive method to measure tumor volume, and response to a targeted therapy was determined. Results: All 13 cases of RCC engrafted and displayed characteristic histology and biomarkers. TSG volume quantified non-invasively by MRI highly correlated with graft weights, providing a unique tool for monitoring orthotopic growth. Moreover, in 2 cases, cancer cells from TSGs metastasized to clinically relevant sites, including bone. Microarray analysis and DNA sequencing demonstrated a high degree of correlation of global gene expression and VHL status between TSGs and parental tumors. Treatment of TSGs with sunitinib significantly decreased graft weight and mean vessel density compared to controls. Conclusions: The TSG model of RCC faithfully recapitulates tumor pathology, gene expression, genetic mutation and drug response. The high engraftment rate and metastatic potential of this authentic model, in conjunction with the ability to generate large first-generation animal cohorts and to quantitate tumor volume at the orthotopic site by MRI, proffer significant advantages compared to other preclinical platforms. Three pairs of tissue slice graftes and parent tumors were included in the study. Tissue slice grafts and parent tumors were preserved in Allprotect tissue reagent (Qiagen, Valencia, CA) at -20Â°C prior to RNA extraction using an AllPrep DNA/RNA/Protein Mini Kit (Qiagen, Valencia, CA). The quality of RNA was determined using an Agilent 2100 Bioanalyzer (Agilent Biotechnologies, Santa Clara, CA). Microarray hybridization was performed using Illumina Human HT-12 v4 Beadchips (Illumina Inc., San Diego, CA) according to the manufacturerâs directions. Expression data was rank invariant normalized using BeadStudio software (Illumina Inc.).

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Identification of ZDHHC14 as a novel tumor suppressor gene commonly downregulated in human cancers

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