RESUMO
Polycomb repressive complex 2 (PRC2) and its methylation of histone 3 at lysine 27 (H3K27me3) play a crucial role in epigenetic regulation of normal development and malignancy. Several factors regulate the recruitment of PRC2 and affects its chromatin modification function. Over the past years, emerging discoveries have portrayed the association of RNA (protein-coding and non-coding) with PRC2 as a critical factor in understanding PRC2 function. With PRC2 being a macromolecular complex of interest in development and diseases, further studies are needed to relate the rapidly evolving PRC2:RNA biology in that scenario. In this review, we summarize the current understanding of different modes of RNA binding by PRC2, and further discuss perspectives, key questions and therapeutic applications of PRC2 binding to RNAs.
Assuntos
Regulação da Expressão Gênica , Proteínas do Grupo Polycomb/metabolismo , RNA/genética , Animais , Humanos , Modelos Biológicos , Proteínas do Grupo Polycomb/genética , Ligação Proteica , RNA/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Pequeno RNA não Traduzido/genética , Pequeno RNA não Traduzido/metabolismoRESUMO
Living cells display dynamic and complex behaviors. To understand their response and to infer novel insights not possible with traditional reductionist approaches, over the last few decades various computational modelling methodologies have been developed. In this chapter, we focus on modelling the dynamic metabolic response, using linear and nonlinear ordinary differential equations, of an engineered Escherichia coli MG1655 strain with plasmid pJBEI-6409 that produces limonene. We show the systems biology steps involved from collecting time-series data of living cells, to dynamic model creation and fitting the model with experimental responses using COPASI software.
Assuntos
Escherichia coli , Software , Limoneno/metabolismo , Simulação por Computador , Escherichia coli/genética , Escherichia coli/metabolismo , Biologia de Sistemas/métodos , Modelos BiológicosRESUMO
Overexpression of PRL-3, an oncogenic phosphatase, was identified as a novel cluster in patients with newly diagnosed multiple myeloma. However, the regulation and oncogenic activities of PRL-3 in multiple myeloma warrant further investigation. Here, we report that IL6 activates STAT3, which acts as a direct transcriptional regulator of PRL-3. Upregulation of PRL-3 increased myeloma cell viability and rephosphorylated STAT3 in a biphasic manner through direct interaction and deactivation of SHP2, thus blocking the gp130 (Y759)-mediated repression of STAT3 activity. Abrogation of PRL-3 reduced myeloma cell survival, clonogenicity, and tumorigenesis, and detailed mechanistic studies revealed "deactivation" of effector proteins such as Akt, Erk1/2, Src, STAT1, and STAT3. Furthermore, loss of PRL-3 efficiently abolished nuclear localization of STAT3 and reduced its occupancy on the promoter of target genes c-Myc and Mcl-1, and antiapoptotic genes Bcl2 and Bcl-xL. PRL-3 also played a role in the acquired resistance of myeloma cells to bortezomib, which could be overcome by PRL-3 silencing. Of clinical relevance, STAT3 and PRL-3 expression was positively correlated in five independent cohorts, and the STAT3 activation signature was significantly enriched in patients with high PRL-3 expression. Furthermore, PRL-3 could be used as a biomarker to identify high-risk patients with multiple myeloma that exhibited poor prognosis and inferior outcome even when treated with novel combinational therapeutics (proteasome inhibitors and immunomodulatory imide drugs). Conclusively, our results support a feedforward mechanism between STAT3 and PRL-3 that prolongs prosurvival signaling in multiple myeloma, and suggest targeting PRL-3 as a valid therapeutic opportunity in multiple myeloma. SIGNIFICANCE: IL6 promotes STAT3-dependent transcriptional upregulation of PRL-3, which in turn re-phosphorylates STAT3 and aberrantly activates STAT3 target genes, leading to bortezomib resistance in multiple myeloma.
Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Interleucina-6/farmacologia , Mieloma Múltiplo/patologia , Proteínas de Neoplasias/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Bortezomib/farmacologia , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Proteínas de Neoplasias/genética , Fosforilação , Prognóstico , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Tirosina Fosfatases/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Natural killer/T-cell lymphoma (NKTCL) is an aggressive non-Hodgkin lymphoma that has been facing limited success with conventional treatments, urging for the discovery of alternative strategies. Recent studies including ours have revealed that EZH2 and JAK-STAT signalling pathways are key contributors to NKTCL pathogenesis. In particular, we found that EZH2 is overexpressed and directly transcriptionally activates the CCND1 gene to confer growth advantage. CCND1 codes for cyclin D1, which complexes with CDK4/6 to promote G1 to S phase transition. Therefore in this study we investigated whether inhibiting both JAK1/2 and CDK4/6, using LEE011 and ruxolitinib respectively is effective in NKTL. We first demonstrate that separate LEE011 and ruxolitinib treatment is sufficient to cause growth inhibition of NKTCL cells. More importantly, we found that there is synergistic growth inhibitory effects on NKTCL cells with combination treatment of LEE011 and ruxolitinib. The results obtained shows that the targeting of both CDK4/6 and JAK1/2 are promising to develop better treatment alternatives for NKTCL.