title: Tumor suppressor SET9 guides the epigenetic plasticity of breast cancer cells and serves as an early-stage biomarker for predicting metastasis.
abstract: During the course of cancer progression, neoplastic cells undergo dynamic and reversible transitions between multiple phenotypic states, and this plasticity is enabled by underlying shifts in epigenetic regulation. Our results identified a negative feedback loop in which SET9 controls DNA methyltransferase-1 protein stability, which represses the transcriptional activity of the SET9 promoter in coordination with Snail. The modulation of SET9 expression in breast cancer cells revealed a connection with E2F1 and the silencing of SET9 was sufficient to complete an epigenetic program that favored epithelial-mesenchymal transition and the generation of cancer stem cells, indicating that SET9 plays a role in modulating breast cancer metastasis. SET9 expression levels were significantly higher in samples from patients with pathological complete remission than in samples from patients with disease recurrence, which indicates that SET9 acts as a tumor suppressor in breast cancer and that its expression may serve as a prognostic marker for malignancy.
authors.affiliation: Department of Biochemistry and Molecular Biology A, School of Biology, University of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain.
authors.forename: M F
authors.initials: MF
authors.lastname: Montenegro
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford, UK.
authors.forename: L
authors.initials: L
authors.lastname: Sánchez-Del-Campo
authors.affiliation: Department of Biochemistry and Molecular Biology A, School of Biology, University of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain.
authors.forename: R
authors.initials: R
authors.lastname: González-Guerrero
authors.affiliation: Department of Pathology, University Hospital Virgen de la Arrixaca, IMIB, Murcia, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Martínez-Barba
authors.affiliation: Department of Surgery, University Hospital Virgen de la Arrixaca, IMIB, Murcia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Piñero-Madrona
authors.affiliation: Molecular Therapy and Biomarkers Research Group, University Hospital Virgen de la Arrixaca, IMIB, Murcia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Cabezas-Herrera
authors.affiliation: Department of Biochemistry and Molecular Biology A, School of Biology, University of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain.
authors.forename: J N
authors.initials: JN
authors.lastname: Rodríguez-López
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D011485:Protein Binding; D012372:ROC Curve; D000071250:Snail Family Transcription Factors / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D000071250:Snail Family Transcription Factors; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human