RESUMO
Sirtuin 3 (SIRT3) deacetylase is a key regulator for chemoresistance in acute myeloid leukemia (AML) cells due to its capability of modulating mitochondrial metabolism and reactive oxygen species (ROS). SIRT3 is de-SUMOylated by SUMO-specific peptidase 1 (SENP1), which enhances its deacetylase activity. Therefore, dysregulation of SIRT3 SUMOylation may lead to fortified chemoresistance in AML. Indeed, SIRT3 de-SUMOylation was induced by chemotherapeutic agents, which in turn, exacerbated resistance against chemotherapies in AML by activating SIRT3 via preventing its proteasome degradation. Furthermore, RNA-seq revealed that expression of a collection of genes was altered by SIRT3 de-SUMOylation including inhibition of transcription factor Hes Family BHLH Transcription Factor 1 (HES1), a downstream substrate of Notch1 signaling pathway, leading to increased fatty acids oxidation (FAO). Moreover, the SENP1 inhibitor momordin-Ic or HES1 overexpression synergized with cytarabine to eradicate AML cells in vitro and in xenograft mouse models. In summary, the current study revealed a novel role of SIRT3 SUMOylation in the regulation of chemoresistance in AML via HES1-dependent FAO and provided a rationale for SIRT3 SUMOylation and FAO targeted interventions to improve chemotherapies in AML.
Assuntos
Leucemia Mieloide Aguda , Sirtuína 3 , Animais , Resistencia a Medicamentos Antineoplásicos/genética , Ácidos Graxos/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos , Sirtuína 3/genética , Sirtuína 3/metabolismo , Sumoilação , Fatores de Transcrição HES-1/genética , Fatores de Transcrição HES-1/metabolismoRESUMO
Although oncogenicity of the stem cell regulator SOX9 has been implicated in many solid tumors, its role in lymphomagenesis remains largely unknown. In this study, SOX9 was overexpressed preferentially in a subset of diffuse large B-cell lymphomas (DLBCLs) that harbor IGH-BCL2 translocations. SOX9 positivity in DLBCL correlated with an advanced stage of disease. Silencing of SOX9 decreased cell proliferation, induced G1/S arrest, and increased apoptosis of DLBCL cells, both in vitro and in vivo. Whole-transcriptome analysis and chromatin immunoprecipitation-sequencing assays identified DHCR24, a terminal enzyme in cholesterol biosynthesis, as a direct target of SOX9, which promotes cholesterol synthesis by increasing DHCR24 expression. Enforced expression of DHCR24 was capable of rescuing the phenotypes associated with SOX9 knockdown in DLBCL cells. In models of DLBCL cell line xenografts, SOX9 knockdown resulted in a lower DHCR24 level, reduced cholesterol content, and decreased tumor load. Pharmacological inhibition of cholesterol synthesis also inhibited DLBCL xenograft tumorigenesis, the reduction of which is more pronounced in DLBCL cell lines with higher SOX9 expression, suggesting that it may be addicted to cholesterol. In summary, our study demonstrated that SOX9 can drive lymphomagenesis through DHCR24 and the cholesterol biosynthesis pathway. This SOX9-DHCR24-cholesterol biosynthesis axis may serve as a novel treatment target for DLBCLs.
Assuntos
Colesterol/genética , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma Difuso de Grandes Células B/genética , Proteínas do Tecido Nervoso/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Fatores de Transcrição SOX9/genética , Vias Biossintéticas , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Proteínas de Fusão Oncogênica/genética , Oncogenes , TranscriptomaRESUMO
There is still an enormous demand for designing materials to the treatment of Parkinson's disease, and dopamine-based injectable polysaccharide hydrogels as localized drug delivery system have huge potential. Here, we developed a facile approach to prepare dopamine-based and polydopamine crosslinked injectable hydrogels by simply oxidizing a mixture of quaternized chitosan, gelatin and dopamine under physiological conditions. These injectable hydrogels showed stable mechanical strength by rheometer and exhibited good degradability evaluated by in vitro degradation test. The chemical structure and morphology of the hydrogels were characterized by FT-IR and SEM. Dopamine as a drug for treating Parkinson's disease and metronidazole as an anti-inflammatory drug were encapsulated in the hydrogel. The release profiles indicated that the injectable hydrogels have great capacity as a carrier for long-term localized release system for dopamine and metronidazole. Furthermore, the cytocompatibility of the hydrogels was confirmed by cell viability and proliferation assays using mouse L929 fibroblast cells. This work provides a new and facile approach to prepare dopamine-based injectable materials which can be used as long-term injectable sustained release system for dopamine as well as anti-inflammatory drug for Parkinson's treatment.
