PMID- 28710449 OWN - NLM STAT- MEDLINE DCOM- 20190115 LR - 20190115 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 7 IP - 1 DP - 2017 Jul 14 TI - Combined deletion and DNA methylation result in silencing of FAM107A gene in laryngeal tumors. PG - 5386 LID - 10.1038/s41598-017-05857-1 [doi] LID - 5386 AB - Larynx squamous cell carcinoma (LSCC) is characterized by complex genotypes, with numerous abnormalities in various genes. Despite the progress in diagnosis and treatment of this disease, 5-year survival rates remain unsatisfactory. Therefore, the extended studies are conducted, with the aim to find genes, potentially implicated in this cancer. In this study, we focus on the FAM107A (3p14.3) gene, since we found its significantly reduced expression in LSCC by microarray profiling (Affymetrix U133 Plus 2.0 array). By RT-PCR we have confirmed complete FAM107A downregulation in laryngeal cancer cell lines (15/15) and primary tumors (21/21) and this finding was further supported by FAM107A protein immunohistochemistry (15/15). We further demonstrate that a combined two hit mechanism including loss of 3p and hypermethylation of FAM107A promoter region (in 9/15 cell lines (p < 0.0001) and in 15/21 primary tumors (p < 0.0001)) prevails in the gene transcriptional loss. As a proof of principle, we show that Decitabine - a hypomethylating agent - restores FAM107A expression (5 to 6 fold increase) in the UT-SCC-29 cell line, characterized by high DNA methylation. Therefore, we report the recurrent inactivation of FAM107A in LSCC, what may suggest that the gene is a promising tumor suppressor candidate involved in LSCC development. FAU - Kiwerska, Katarzyna AU - Kiwerska K AD - Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznan, Poland. katarzyna.kiwerska@igcz.poznan.pl. AD - Department of Tumor Pathology, Greater Poland Cancer Center, Garbary 15, 61-866, Poznan, Poland. katarzyna.kiwerska@igcz.poznan.pl. FAU - Szaumkessel, Marcin AU - Szaumkessel M AD - Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznan, Poland. FAU - Paczkowska, Julia AU - Paczkowska J AD - Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznan, Poland. FAU - Bodnar, Magdalena AU - Bodnar M AD - Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Curie-Sklodowskiej 9, 85-094, Bydgoszcz, Poland. AD - Department of Otolaryngology and Laryngeal Oncology, Poznan University of Medical Sciences, Przybyszewskiego 49, 60-355, Poznan, Poland. FAU - Byzia, Ewa AU - Byzia E AD - Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznan, Poland. FAU - Kowal, Ewelina AU - Kowal E AD - Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznan, Poland. FAU - Kostrzewska-Poczekaj, Magdalena AU - Kostrzewska-Poczekaj M AD - Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznan, Poland. FAU - Janiszewska, Joanna AU - Janiszewska J AD - Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznan, Poland. FAU - Bednarek, Kinga AU - Bednarek K AD - Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznan, Poland. FAU - Jarmuz-Szymczak, Malgorzata AU - Jarmuz-Szymczak M AD - Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznan, Poland. AD - Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Szamarzewskiego 82/84, 60-569, Poznan, Poland. FAU - Kalinowicz, Ewelina AU - Kalinowicz E AD - Department of Otolaryngology and Laryngeal Oncology, Poznan University of Medical Sciences, Przybyszewskiego 49, 60-355, Poznan, Poland. FAU - Wierzbicka, Malgorzata AU - Wierzbicka M AD - Department of Otolaryngology and Laryngeal Oncology, Poznan University of Medical Sciences, Przybyszewskiego 49, 60-355, Poznan, Poland. FAU - Grenman, Reidar AU - Grenman R AD - Department of Otorhinolaryngology, Head and Neck Surgery and Department of Medical Biochemistry, Turku University Central Hospital and Turku University, PO Box 52 FI-20521, Turku, Finland. FAU - Szyfter, Krzysztof AU - Szyfter K AD - Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznan, Poland. AD - Department of Audiology and Phoniatrics, Poznan University of Medical Sciences, Przybyszewskiego 49, 60-355, Poznan, Poland. FAU - Marszalek, Andrzej AU - Marszalek A AD - Oncologic Pathology and Prophylaxis Poznan University of Medical Sciences & Greater Poland Cancer Center, Garbary 15, 61-866, Poznan, Poland. FAU - Giefing, Maciej AU - Giefing M AD - Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479, Poznan, Poland. AD - Department of Otolaryngology and Laryngeal Oncology, Poznan University of Medical Sciences, Przybyszewskiego 49, 60-355, Poznan, Poland. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170714 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (FAM107A protein, human) RN - 0 (Neoplasm Proteins) RN - 0 (Nuclear Proteins) RN - 776B62CQ27 (Decitabine) SB - IM MH - Antimetabolites, Antineoplastic/pharmacology MH - Carcinoma, Squamous Cell/*genetics/metabolism/pathology MH - Cell Line, Tumor MH - Decitabine/pharmacology MH - Gene Expression Profiling MH - *Gene Expression Regulation, Neoplastic MH - Genes, Tumor Suppressor MH - Humans MH - Laryngeal Neoplasms/*genetics/metabolism/pathology MH - Methylation/drug effects MH - Microarray Analysis MH - Neoplasm Proteins/*genetics/metabolism MH - Neoplasm Staging MH - Nuclear Proteins/agonists/*genetics/metabolism MH - Phosphorylation/drug effects MH - Promoter Regions, Genetic MH - *Protein Processing, Post-Translational PMC - PMC5511162 COIS- The authors declare that they have no competing interests. EDAT- 2017/07/16 06:00 MHDA- 2019/01/16 06:00 PMCR- 2017/07/14 CRDT- 2017/07/16 06:00 PHST- 2017/01/19 00:00 [received] PHST- 2017/06/05 00:00 [accepted] PHST- 2017/07/16 06:00 [entrez] PHST- 2017/07/16 06:00 [pubmed] PHST- 2019/01/16 06:00 [medline] PHST- 2017/07/14 00:00 [pmc-release] AID - 10.1038/s41598-017-05857-1 [pii] AID - 5857 [pii] AID - 10.1038/s41598-017-05857-1 [doi] PST - epublish SO - Sci Rep. 2017 Jul 14;7(1):5386. doi: 10.1038/s41598-017-05857-1.