MCPH1 maintains long‐term epigenetic silencing of ANGPT2 in chronic lymphocytic leukemia. (9th March 2015)

• Record Type: Journal Article
• Authors: Kopparapu, Pradeep Kumar; Miranda, Caroline; Fogelstrand, Linda; Mishra, Kankadeb; Andersson, Per‐Ola; Kanduri, Chandrasekhar; Kanduri, Meena
• Is Part Of: FEBS journal. Volume 282:Number 10(2015)
• Page Start: 1939
• Page End: 1952
• Publication Date: 2015-03-09
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.13245
• Languages: English
• ISSNs: 1742-464X

Abstract

<abstract abstract-type="main" id="febs13245-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>The microcephalin gene (<italic>MCPH1</italic>) [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 <italic>MCPH1</italic> overlaps with the <italic>ANGPT2</italic> transcription unit on the same chromosome but in the opposite orientation, we wanted to study the functional role of <italic>MCPH1</italic> in regulation of <italic>ANGPT2</italic> in CLL. The mRNA expression levels of <italic>MCPH1</italic> and <italic>ANGPT2</italic>, including the <italic>MCPH1</italic> target gene <italic>hTERT</italic>, showed significant differences between two prognostic groups, i.e. <italic>IGHV</italic>‐mutated and <italic>IGHV</italic>‐unmutated (<italic>P </italic>=<italic> </italic>0.007 for <italic>MCPH1</italic>, <italic> P </italic>=<italic> </italic>0.0002 for <italic>ANGPT2</italic>, and <italic>P </italic>=<italic> </italic>0.00001 for <italic>hTERT</italic>), in which the expression level of <italic>MCPH1</italic> was inversely correlated with the expression levels of <italic>hTERT</italic> and <italic>ANGPT2</italic>. Downregulation of <italic>MCPH1</italic> resulted in upregulation of <italic>ANGPT2</italic>, accompanied by loss of its promoter methylation. Using chromatin immunoprecipitation and coimmunoprecipitation assays, we found that MCPH1 binds to the <italic>ANGPT2</italic> promoter and recruits DNA methyltransferases, thereby silencing <italic>ANGPT2</italic>. Thus, our data suggest a novel function for <italic>MCPH1</italic> in regulating and maintaining <italic>ANGPT2</italic> silencing in CLL through regulation of promoter DNA methylation.</p> </abstract>