RESUMO
BACKGROUND: Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder characterized by the accumulation of free cholesterol in lysosomes. There are currently no effective FDA-approved treatments for NPC, although in the last years the inhibition of histone deacetylases (HDACs) has emerged as a potential treatment for this disease. However, the molecular mechanisms that deregulate HDAC activity in NPC disease are unknown. Previously our group had shown that the proapoptotic tyrosine kinase c-Abl signaling is activated in NPC neurons. Here, we demonstrate that c-Abl activity increases HDAC2 levels inducing neuronal gene repression of key synaptic genes in NPC models. RESULTS: Our data show that: i) HDAC2 levels and activity are increased in NPC neuronal models and in Npc1(-/-) mice; ii) inhibition of c-Abl or c-Abl deficiency prevents the increase of HDAC2 protein levels and activity in NPC neuronal models; iii) c-Abl inhibition decreases the levels of HDAC2 tyrosine phosphorylation; iv) treatment with methyl-ß-cyclodextrin and vitamin E decreases the activation of the c-Abl/HDAC2 pathway in NPC neurons; v) in vivo treatment with two c-Abl inhibitors prevents the increase of HDAC2 protein levels in the brain of Npc1(-/-) mice; and vi) c-Abl inhibition prevents HDAC2 recruitment to the promoter of neuronal genes, triggering an increase in their expression. CONCLUSION: Our data show the involvement of the c-Abl/HDAC2 signaling pathway in the regulation of neuronal gene expression in NPC neuronal models. Thus, inhibition of c-Abl could be a pharmacological target for preventing the deleterious effects of increased HDAC2 levels in NPC disease.
Assuntos
Histona Desacetilase 2/genética , Neurônios/metabolismo , Doença de Niemann-Pick Tipo C/genética , Proteínas Proto-Oncogênicas c-abl/genética , Animais , Colesterol/genética , Colesterol/metabolismo , Ciclodextrinas/administração & dosagem , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Histona Desacetilase 2/biossíntese , Humanos , Lisossomos/metabolismo , Camundongos , Neurônios/patologia , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Doença de Niemann-Pick Tipo C/patologia , Proteínas Proto-Oncogênicas c-abl/biossíntese , Transdução de Sinais/efeitos dos fármacos , Vitamina E/administração & dosagemRESUMO
Early growth response-1 (Egr-1) and the non-receptor protein tyrosine kinase (c-Abl) are 2 response genes that can act as regulators of cell growth and apoptosis in response to stress. Both Egr-1 and c-Abl regulate cell proliferation and survival in different types of cancer cells. To study the effect of overexpression of EGR-1 on the activity of c-Abl in prostate cancer cells, human PC-3 and LNCaP cells were transfected with a control vector or a vector containing the murine Egr-1 cDNA and assessed for the expression of the c-Abl gene. Cells overexpressing Egr-1 were studied with respect to apoptosis (Annexin V)/DEVDase activity, Egr-1/c-Abl activation (western blotting) and cell proliferation (MTT assay). The cells were exposed to tumor necrosis factor α (TNF-α), a known inductor of Egr-1, to c-Abl inhibitor STI-571 and to small interfering RNA (siRNA)-Egr-1, respectively. The results from our studies strongly suggest that overexpression of Egr-1 decreased c-Abl activity independent of endogenous Egr-1 inhibition by siRNA-Egr-1.