Epigenetic Alterations in Fanconi Anaemia : Role in Pathophysiology and Therapeutic Potential
Belo, Hélio (Universidade Nova de Lisboa. Faculdade de Ciências Médicas)
Silva, Gabriela (Universidade Nova de Lisboa. Faculdade de Ciências Médicas)
Cardoso, Bruno A. (Universidade Nova de Lisboa. Faculdade de Ciências Médicas)
Porto, Beatriz (Instituto de Ciências Biomédicas de Abel Salazar (Porto, Portugal))
Minguillón Pedreño, Jordi (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Barbot, José (Centro Hospitalar do Porto (Porto, Portugal))
Coutinho, Jorge (Centro Hospitalar do Porto (Porto, Portugal))
Casado, José A. (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (Espanya))
Benedito, Manuela (Centro Hospitalar e Universitário de Coimbra (Coimbra, Portugal))
Saturnino, Hema (Centro Hospitalar e Universitário de Coimbra (Coimbra, Portugal))
Costa, Emília (Centro Hospitalar do Porto (Porto, Portugal))
Bueren, Juan (Centro Hospitalar do Porto (Porto, Portugal))
Surrallés i Calonge, Jordi (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Almeida, António (Universidade Nova de Lisboa. Faculdade de Ciências Médicas)

Data:	2015
Resum:	Fanconi anaemia (FA) is an inherited disorder characterized by chromosomal instability. The phenotype is variable, which raises the possibility that it may be affected by other factors, such as epigenetic modifications. These play an important role in oncogenesis and may be pharmacologically manipulated. Our aim was to explore whether the epigenetic profiles in FA differ from non-FA individuals and whether these could be manipulated to alter the disease phenotype. We compared expression of epigenetic genes and DNA methylation profile of tumour suppressor genes between FA and normal samples. FA samples exhibited decreased expression levels of genes involved in epigenetic regulation and hypomethylation in the promoter regions of tumour suppressor genes. Treatment of FA cells with histone deacetylase inhibitor Vorinostat increased the expression of DNM3Tβ and reduced the levels of CIITA and HDAC9, PAK1, USP16, all involved in different aspects of epigenetic and immune regulation. Given the ability of Vorinostat to modulate epigenetic genes in FA patients, we investigated its functional effects on the FA phenotype. This was assessed by incubating FA cells with Vorinostat and quantifying chromosomal breaks induced by DNA cross-linking agents. Treatment of FA cells with Vorinostat resulted in a significant reduction of aberrant cells (81% on average). Our results suggest that epigenetic mechanisms may play a role in oncogenesis in FA. Epigenetic agents may be helpful in improving the phenotype of FA patients, potentially reducing tumour incidence in this population.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Epigenetics ; Gene expression ; DNA methylation ; Tumor suppressor genes ; Gene regulation ; DNA ; Histones ; Anemia
Publicat a:	PloS one, Vol. 10, Num. 10 (October 2015) , p. 1-13, ISSN 1932-6203

DOI: 10.1371/journal.pone.0139740
PMID: 26466379

13 p, 2.1 MB

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