Tribbles 2 mediates cisplatin sensitivity and DNA damage response in epithelial ovarian cancer

• Published in: International journal of cancer 2017-10, Vol.141 (8), p.1600-1614
• Main Authors: Kritsch, Daniel, Hoffmann, Franziska, Steinbach, Daniel, Jansen, Lars, Mary Photini, Stella, Gajda, Mieczyslaw, Mosig, Alexander S., Sonnemann, Jürgen, Peters, Sven, Melnikova, Margarita, Thomale, Jürgen, Dürst, Matthias, Runnebaum, Ingo B., Häfner, Norman
• Format: Article
• Language: English
• Subjects: Activation; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Calcium-Calmodulin-Dependent Protein Kinases - biosynthesis; Calcium-Calmodulin-Dependent Protein Kinases - genetics; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cancer; Carcinoma, Ovarian Epithelial; Cell cycle; Cell Line, Tumor; Cell lines; Chemotherapy; Cisplatin; Cisplatin - pharmacology; CpG islands; Cyclin-Dependent Kinase Inhibitor p21 - biosynthesis; Deoxyribonucleic acid; DNA; DNA adducts; DNA Adducts - biosynthesis; DNA Damage; DNA damage response; DNA Methylation; Drug Resistance, Neoplasm - genetics; Female; G2 Phase; Gene expression; Gene silencing; Genes; Genomes; GTP-binding protein; Humans; Intracellular Signaling Peptides and Proteins - biosynthesis; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; M Phase Cell Cycle Checkpoints; Medical research; Methylation; Neoplasms, Glandular and Epithelial - drug therapy; Neoplasms, Glandular and Epithelial - genetics; Neoplasms, Glandular and Epithelial - metabolism; Nucleotide excision repair; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; platin resistance; Polymerase chain reaction; prognosis; Proteome - metabolism; Remission; Sensitivity; Signal transduction; Stratification; Survivin; Taxanes; Transduction; Tumor Cells, Cultured; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.30860

Aim was to identify methylated genes with functional involvement in cisplatin‐resistance development of epithelial ovarian cancer (EOC). Genome‐wide analyses of hypermethylated CpG‐islands in resistant cell lines in combination with qRT‐PCR analyses were used to identify epigenetically silenced genes. EOC‐Type‐II tumors were analyzed for gene methylation and expression and TCGA data were interrogated in‐silico. Experiments revealed 37 commonly hypermethylated genes in resistant cells of which Tribbles 2 (TRIB2) showed the most pronounced downregulation on mRNA level and was characterized further. TRIB2 showed a reactivation after 5′‐Aza‐Cytidine treatment in resistant cells but a cisplatin‐dependent, prominent upregulation on mRNA level in sensitive cells, only. Re‐expression in resistant A2780 cells increased the sensitivity to cisplatin and other DNA‐damaging agents, but not taxanes. Contrary, knockdown of TRIB2 increased resistance to cisplatin in sensitive cells. TRIB2 was involved in the induction of a cisplatin‐dependent cell cycle arrest and apoptosis by influencing p21 and survivin expression. An increased Pt‐DNA‐adduct formation in TRIB2 re‐expressing cells did not translate in higher levels of dsDNA damage (yH2AX‐foci). Thus, TRIB2 is potentially involved in the signal transduction from nucleotide excision repair of intrastrand cross links. Importantly, patient stratification of two homogenous cohorts of EOC‐Type‐II patients from Jena (n = 38) and the TCGA (n = 149) by TRIB2 mRNA expression consistently revealed a significantly decreased PFS for patients with low TRIB2 levels (log‐rank p