RESUMO
Nucleophosmin (NPM1) is a multifunctional histone chaperone that can activate acetylation-dependent transcription from chromatin templates in vitro. p300-mediated acetylation of NPM1 has been shown to further enhance its transcription activation potential. Acetylated and total NPM1 pools are increased in oral squamous cell carcinoma. However, the role of NPM1 or its acetylated form (AcNPM1) in transcriptional regulation in cells and oral tumorigenesis is not fully elucidated. Using ChIP-seq analyses, we provide the first genome-wide profile of AcNPM1 and show that AcNPM1 is enriched at transcriptional regulatory elements. AcNPM1 co-occupies marks of active transcription at promoters and DNase I hypersensitive sites at enhancers. In addition, using a high-throughput protein interaction profiling approach, we show that NPM1 interacts with RNA Pol II, general transcription factors, mediator subunits, histone acetyltransferase complexes, and chromatin remodelers. NPM1 histone chaperone activity also contributes to its transcription activation potential. Further, NPM1 depletion leads to decreased AcNPM1 occupancy and reduced expression of genes required for proliferative, migratory and invasive potential of oral cancer cells. NPM1 depletion also abrogates the growth of orthotopic tumors in mice. Collectively, these results establish that AcNPM1 functions as a coactivator during during RNA polymerase II-driven transcription and regulates the expression of genes that promote oral tumorigenesis.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Regulação da Expressão Gênica/fisiologia , Chaperonas de Histonas/metabolismo , Neoplasias Bucais/genética , Nucleofosmina/metabolismo , Animais , Carcinogênese/metabolismo , Carcinoma de Células Escamosas/genética , Montagem e Desmontagem da Cromatina/genética , Montagem e Desmontagem da Cromatina/fisiologia , Regulação da Expressão Gênica/genética , Histonas/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas/genéticaRESUMO
Antimicrobial peptides (brevinin1 HYba1 and brevinin1 HYba2) identified from the skin secretion of an endemic frog species of Western Ghats were studied against fish pathogens. Post-translational modifications such as c-terminal amidation and cyclization of the peptides were enhanced on the activity against Aeromonas sobria. Based on the Minimum inhibitory concentration (3 µM), cyclic amidated brevinin Hyba2 was identified as the most promising antimicrobial agent against A. sobria and can be developed further as a lead drug molecule.
