Regulação da expressão da histona H2A.Z é mediada pelo SIRT1 no cancro da próstata

Dentro dos mecanismos clássicos de carácter epigénetico associado à carcinogénese, aqueles que dizem respeito às alterações de variantes de histonas são os menos compreendidos. Contudo, nos últimos anos, a variante H2A.Z e a sua forma acetilada têm surgido como um elemento importante no desenvolvimento e progressão neoplásica, nomeadamente em cancro da mama e da próstata, tendo sido sugeridas como alvos terapêuticos em carcinoma mamário. Com este trabalho, verificou-se que a sobrexpressão da H2A.Z em cancro da próstata está relacionada com a expressão comprometida do SIRT1, um gene supressor tumoral condicional, estando reciprocamente e inversamente relacionados. Na verdade, mecanismos epigenéticos, principalmente modificações pós-translacionais das histonas, estão envolvidos nesta desregulação, impedindo a diminuição da variante de histona promovida pela sirtuina 1, maioritariamente através da degradação proteosomal da primeira. Assim, drogas modificadoras dos padrões epigenéticos, em conjunto com moduladores enzimáticos da sirtuina 1, são capazes de restaurar as suas funções normais, diminuindo os níveis da variante oncogénica H2A.Z e dos seus alvos, como o C-MYC, e podem constituir ferramentas relevantes para a terapia dirigida de pacientes com cancro da próstata.

Autores e afiliações:
Tiago Baptista1,2, Inês Graça1,2,4, Elsa J. Sousa1,2, Ana I. Oliveira1,2, Natália R. Costa1,2, Pedro Costa-Pinheiro1,2, Francisco Amado5, Rui Henrique1,3,6 and Carmen Jerónimo1,2,6

1Cancer Epigenetics Group, Research Center, Portuguese Oncology Institute – Porto, Portugal

2Department of Genetics, Portuguese Oncology Institute – Porto, Portugal

3Department of Pathology, Portuguese Oncology Institute – Porto, Portugal

4School of Allied Health Sciences ESTSP, Polytechnic of Porto

5Department of Chemistry, Universidade de Aveiro, Campus Universitário de Santiago, Aveiro, Portugal

6Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto, Portugal

Abstract:
Histone variants seem to play a major role in gene expression regulation. In prostate cancer, H2A.Z and its acetylated form are implicated in oncogenes’ upregulation. SIRT1, which may act either as tumor suppressor or oncogene, reduces H2A.Z levels in cardiomyocytes, via proteasome-mediated degradation, and this mechanism might be impaired in prostate cancer cells due to sirtuin 1 downregulation. Thus, we aimed to characterize the mechanisms underlying H2A.Z and SIRT1 deregulation in prostate carcinogenesis and how they interact. We found that H2AFZ and SIRT1 were up- and downregulated, respectively, at transcript level in primary prostate cancer and high-grade prostatic intraepithelial neoplasia compared to normal prostatic tissues. Induced SIRT1 overexpression in prostate cancer cell lines resulted in almost complete absence of H2A.Z. Inhibition of mTOR had a modest effect on H2A.Z levels, but proteasome inhibition prevented the marked reduction of H2A.Z due to sirtuin 1 overexpression. Prostate cancer cells exposed to epigenetic modifying drugs trichostatin A, alone or combined with 5-aza- 2’-deoxycytidine, increased H2AFZ transcript, although with a concomitant decrease in protein levels. Conversely, SIRT1 transcript and protein levels increased after exposure. ChIP revealed an increase of activation marks within the TSS region for both genes. Remarkably, inhibition of sirtuin 1 with nicotinamide, increased H2A.Z levels, whereas activation of sirtuin 1 by resveratrol led to an abrupt decrease in H2A.Z. Finally, protein-ligation assay showed that exposure to epigenetic modifying drugs fostered the interaction between sirtuin 1 and H2A.Z. We concluded that sirtuin 1 and H2A.Z deregulation in prostate cancer are reciprocally related. Epigenetic mechanisms, mostly histone post-translational modifications, are likely involved and impair sirtuin 1-mediated downregulation of H2A.Z via proteasome-mediated degradation. Epigenetic modifying drugs in conjunction with enzymatic modulators are able to restore the normal functions of sirtuin 1 and might constitute relevant tools for targeted therapy of prostate cancer patients.

Revista:
Oncotarget

Link:
http://www.ncbi.nlm.nih.gov/pubmed/24127549