RESUMO
Metabolic changes are linked to epigenetic reprogramming and play important roles in several tumor types. PGC-1α is a transcriptional coactivator controlling mitochondrial biogenesis and is linked to oxidative phosphorylation. We provide evidence that melanoma models with elevated PGC-1α levels are characteristic of the proliferative phenotype and are sensitive to bromodomain and extra-terminal domain (BET) inhibitor treatment. A super-enhancer region highly occupied by the BET family member BRD4 was identified for the PGC-1α gene. BET inhibitor treatment prevented this interaction, leading to a dramatic reduction of PGC-1α expression. Accordingly, BET inhibition diminished respiration and mitochondrial function in cells. In vivo, melanoma models with high PGC-1α expression strongly responded to BET inhibition by reduction of PGC-1α and impaired tumor growth. Altogether, our findings identify epigenetic regulatory elements that define a subset of melanomas with high sensitivity to BET inhibition, which opens up the opportunity to define melanoma patients most likely to respond to this treatment, depending on their tumor characteristics.
Assuntos
Antineoplásicos/farmacologia , Elementos Facilitadores Genéticos/genética , Melanoma/genética , Proteínas Nucleares/antagonistas & inibidores , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Fatores de Transcrição/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Azepinas/farmacologia , Azepinas/uso terapêutico , Benzodiazepinas/farmacologia , Benzodiazepinas/uso terapêutico , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Nucleares/metabolismo , Seleção de Pacientes , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ligação Proteica/genética , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fatores de Transcrição/metabolismo , Resultado do Tratamento , Triazóis/farmacologia , Triazóis/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: Periprocedural management of warfarin remains challenging in patients requiring electrophysiological device surgery. For patients at high risk of thromboembolic events, guidelines recommend bridging therapy with heparin; however, this strategy is associated with a high risk of pocket hematoma. This paper systematically reviews studies appraising the risk of pocket hematoma with different perioperative anticoagulation strategies. METHODS: All relevant studies identified in MEDLINE/PubMed, The Cochrane Collaboration CENTRAL, clinicaltrials.org and in bibliographies of key articles. Estimates were combined using a fixed effects model. Heterogeneity was assessed by p values of χ2 statistics and I2. Publication bias was assessed by visual examination of funnel plots and by Egger test. Fifteen studies enrolling 5911 patients met all inclusion criteria and were included in this review. RESULTS: Heparin bridging compared with no heparin was associated with increased risk of pocket hematoma (OR = 4.47, 95% CI 3.21-6.23, p < 0.00001), and prolonged hospital stay (9.13 ± 1.9 days vs. 5.11 ± 1 .39 days, p < 0.00001). Warfarin continuation was not associated with increased pocket hematoma compared to warfarin discontinuation (p = 0.38), but was associated with reduced risk of pocket hematoma compared with heparin bridging (OR = 0.37, 95% CI 0.2-0.69, p = 0.002). Thromboembolic complications were reduced with heparin bridging vs. no heparin (0.50% vs.1.07%, p = 0.02), and no significant differences were reported between heparin bridging vs. warfarin continuation (p = 0.83). CONCLUSIONS: Heparin bridging is associated with a higher risk of pocket hematoma and a prolonged hospital stay. Perioperative continuation of warfarin reduces the occurrence of pocket hematoma compared with heparin bridging without any significant differences in thromboembolic complications.