title: MCPH1 maintains long-term epigenetic silencing of ANGPT2 in chronic lymphocytic leukemia.
abstract: The microcephalin gene (MCPH1) [also known as inhibitor of human telomerase reverse transcriptase (hTERT) expression] is a tumor suppressor gene that is functionally involved in the DNA damage response. Angiopoietin 2 (ANGPT2) is a crucial factor regulating tumor angiopoiesis. Deregulation of angiogenesis is one of the hallmarks of many cancers, including chronic lymphocytic leukemia (CLL). In CLL, ANGPT2 is a well-studied potential prognostic marker. As MCPH1 overlaps with the ANGPT2 transcription unit on the same chromosome but in the opposite orientation, we wanted to study the functional role of MCPH1 in regulation of ANGPT2 in CLL. The mRNA expression levels of MCPH1 and ANGPT2, including the MCPH1 target gene hTERT, showed significant differences between two prognostic groups, i.e. IGHV-mutated and IGHV-unmutated (P = 0.007 for MCPH1, P = 0.0002 for ANGPT2, and P = 0.00001 for hTERT), in which the expression level of MCPH1 was inversely correlated with the expression levels of hTERT and ANGPT2. Downregulation of MCPH1 resulted in upregulation of ANGPT2, accompanied by loss of its promoter methylation. Using chromatin immunoprecipitation and coimmunoprecipitation assays, we found that MCPH1 binds to the ANGPT2 promoter and recruits DNA methyltransferases, thereby silencing ANGPT2. Thus, our data suggest a novel function for MCPH1 in regulating and maintaining ANGPT2 silencing in CLL through regulation of promoter DNA methylation.
authors.affiliation: Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy, Gothenburg University, Sweden.
authors.forename: Pradeep Kumar
authors.initials: PK
authors.lastname: Kopparapu
authors.affiliation: Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy, Gothenburg University, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Miranda
authors.affiliation: Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy, Gothenburg University, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Fogelstrand
authors.affiliation: Department of Medical and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, Gothenburg University, Sweden.
authors.forename: Kankadeb
authors.initials: K
authors.lastname: Mishra
authors.affiliation: Department of Internal Medicine and Oncology, Borås Hospital, Sweden.|Department of Medicine, Sahlgrenska Academy, Gothenburg University, Sweden.
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Andersson
authors.affiliation: Department of Medical and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, Gothenburg University, Sweden.
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Kanduri
authors.affiliation: Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy, Gothenburg University, Sweden.
authors.forename: Meena
authors.initials: M
authors.lastname: Kanduri
mesh_terms: D042702:Angiopoietin-2 / Q000235:genetics*; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: C586513:ANGPT2 protein, human; D042702:Angiopoietin-2; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger
keywords: ANGPT2; DNA methylation; MCPH1; chronic lymphocytic leukemia