ABSTRACT
BACKGROUND: Genetic aberrations in DNA repair genes are linked to cancer, but less is reported about epigenetic regulation of DNA repair and functional consequences. We investigated the intragenic methylation loss at the three prime repair exonuclease 2 (TREX2) locus in laryngeal (n = 256) and colorectal cancer cases (n = 95) and in pan-cancer data from The Cancer Genome Atlas (TCGA). RESULTS: Significant methylation loss at an intragenic site of TREX2 was a frequent trait in both patient cohorts (p = 0.016 and < 0.001, respectively) and in 15 out of 22 TCGA studies. Methylation loss correlated with immunohistochemically staining for TREX2 (p < 0.0001) in laryngeal tumors and improved overall survival of laryngeal cancer patients (p = 0.045). Chromatin immunoprecipitation, demethylation experiments, and reporter gene assays revealed that the region of methylation loss can function as a CCAAT/enhancer binding protein alpha (CEBPA)-responsive enhancer element regulating TREX2 expression. CONCLUSIONS: The data highlight a regulatory role of TREX2 DNA methylation for gene expression which might affect incidence and survival of laryngeal cancer. Altered TREX2 protein levels in tumors may affect drug-induced DNA damage repair and provide new tailored therapies.
Subject(s)
DNA Methylation , Exodeoxyribonucleases/genetics , Exodeoxyribonucleases/metabolism , Laryngeal Neoplasms/mortality , Phosphoproteins/genetics , Phosphoproteins/metabolism , Up-Regulation , Aged , Cell Line, Tumor , DNA Repair , Epigenesis, Genetic , Exodeoxyribonucleases/chemistry , Female , Gene Expression Regulation, Neoplastic , HCT116 Cells , Humans , Laryngeal Neoplasms/genetics , Laryngeal Neoplasms/metabolism , Male , Middle Aged , Phosphoproteins/chemistry , Protein Domains , Survival AnalysisSubject(s)
Carcinoma, Squamous Cell , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Lymphadenitis/virology , Aged , Herpesvirus 4, Human , Humans , Lymphatic Metastasis , Male , Neoplasms, Second Primary , Simplexvirus , Virus Diseases/etiologyABSTRACT
Although disease management of head and neck squamous cell carcinomas (HNSCC) has improved significantly, therapy resistance leading to tumor recurrence still counteracts improvement of long-term survival. Consequently, identification of molecular markers that signal increased risk of treatment failure or, which can be exploited by targeted therapy, is urgently needed. Survivin is strongly expressed in HNSCC, and its proposed dual role as an apoptosis inhibitor and a mitotic effector positioned survivin in the front line of cancer research. Notably, survivin is detected as a cytoplasmic and as a nuclear protein in HNSCC patients, which stimulated numerous studies to investigate and to speculate on the functional and prognostic significance of its dynamic localization. This review focuses on our current understanding of the molecular mechanisms regulating survivin's intracellular localization and discusses its potential prognostic and therapeutic relevance for head and neck cancer.
Subject(s)
Biomarkers, Tumor , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/therapy , Microtubule-Associated Proteins/metabolism , Neoplasm Proteins/metabolism , Animals , Humans , Inhibitor of Apoptosis Proteins , Microtubule-Associated Proteins/genetics , Neoplasm Proteins/genetics , Prognosis , SurvivinABSTRACT
Survivin is described as a bifunctional protein inhibiting apoptosis and regulating mitosis. However, the biological functions and contributions to cancer progression of survivin splice variants are controversially discussed. We here show that the intracellular localization of these splice variants depends on a Crm1-dependent nuclear export signal (NES) present in survivin, surviving(-2B) and survivin(-3B), but absent in survivin(-deltaEx3) and survivin(-2alpha). Survivin isoforms lack an active nuclear import signal and are able to enter the nucleus by passive diffusion. Only survivin(-3B) but none of the other splice variants is cytoprotective and able to efficiently interact with chromosomal passenger complex (CPC) proteins. The NES together with efficient CPC formation is required for the cytoprotective activity of survivin isoforms, as well as for their correct localization and function during cell division. In the tumours from breast, colorectal, head and neck cancer, lymphoma and leukemia patients, survivin and survivin(-2B) were found overexpressed. However, survivin was the predominant form detected, and the other survivin isoforms were only expressed at low levels in tumours. Our data provide a molecular rationale for the localization and activity of survivin variants, and conclude that survivin isoforms are unlikely to modulate survivin in trans in cancer patients.
