RESUMEN
BACKGROUND & AIMS: Aberrant DNA methylation is frequent in colorectal cancer (CRC), but underlying mechanisms and pathologic consequences are poorly understood. METHODS: We disrupted active DNA demethylation genes Tet1 and/or Tdg from ApcMin mice and characterized the methylome and transcriptome of colonic adenomas. Data were compared to human colonic adenocarcinomas (COAD) in The Cancer Genome Atlas. RESULTS: There were increased numbers of small intestinal adenomas in ApcMin mice expressing the TdgN151A allele, whereas Tet1-deficient and Tet1/TdgN151A-double heterozygous ApcMin colonic adenomas were larger with features of erosion and invasion. We detected reduction in global DNA hypomethylation in colonic adenomas from Tet1- and Tdg-mutant ApcMin mice and hypermethylation of CpG islands in Tet1-mutant ApcMin adenomas. Up-regulation of inflammatory, immune, and interferon response genes was present in Tet1- and Tdg-mutant colonic adenomas compared to control ApcMin adenomas. This up-regulation was also seen in murine colonic organoids and human CRC lines infected with lentiviruses expressing TET1 or TDG short hairpin RNA. A 127-gene inflammatory signature separated colonic adenocarcinomas into 4 groups, closely aligned with their microsatellite or chromosomal instability and characterized by different levels of DNA methylation and DNMT1 expression that anticorrelated with TET1 expression. Tumors with the CpG island methylator phenotype (CIMP) had concerted high DNMT1/low TET1 expression. TET1 or TDG knockdown in CRC lines enhanced killing by natural killer cells. CONCLUSIONS: Our findings reveal a novel epigenetic regulation, linked to the type of genomic instability, by which TET1/TDG-mediated DNA demethylation decreases methylation levels and inflammatory/interferon/immune responses. CIMP in CRC is triggered by an imbalance of methylating activities over demethylating activities. These mice represent a model of CIMP CRC.
Asunto(s)
Adenocarcinoma , Adenoma , Neoplasias del Colon , Neoplasias Colorrectales , Animales , Humanos , Ratones , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenoma/genética , Adenoma/patología , Carcinogénesis/genética , Transformación Celular Neoplásica/genética , Neoplasias del Colon/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Islas de CpG/genética , Metilación de ADN , Proteínas de Unión al ADN/genética , Epigénesis Genética , Oxigenasas de Función Mixta/genética , Fenotipo , Proteínas Proto-Oncogénicas/genéticaRESUMEN
In this study, using Jurkat cells, we show that DISC1 (disrupted in schizophrenia 1) and Girdin (girders of actin filament) are essential for typical actin accumulation at the immunological synapse. Furthermore, DISC1, Girdin and dynein are bound in a complex. Although this complex initially forms as a central patch at the synapse, it relocates to a peripheral ring corresponding to the peripheral supramolecular activation cluster (pSMAC). In the absence of DISC1, the classic actin ring does not form, cell spreading is blocked, and the dynein complex fails to relocate to the pSMAC. A similar effect is seen when Girdin is deleted. When cells are treated with inhibitors of actin polymerization, the dynein-NDE1 complex is lost from the synapse and the microtubule-organizing center fails to translocate, suggesting that actin and dynein might be linked. Upon stimulation of T cell receptors, DISC1 becomes associated with talin, which likely explains why the dynein complex colocalizes with the pSMAC. These results show that the DISC1-Girdin complex regulates actin accumulation, cell spreading and distribution of the dynein complex at the synapse.This article has an associated First Person interview with the first author of the paper.
Asunto(s)
Citoesqueleto , Microtúbulos , Actinas/metabolismo , Citoesqueleto/metabolismo , Humanos , Sinapsis Inmunológicas/metabolismo , Proteínas Asociadas a Microtúbulos , Microtúbulos/metabolismo , Proteínas del Tejido Nervioso/genética , Transducción de SeñalRESUMEN
Natural killer (NK) cells have crucial roles in the innate immunosurveillance of cancer and viral infections. They are 'first responders' that can spontaneously recognize abnormal cells in the body, rapidly eliminate them through focused cytotoxicity mechanisms and potently produce pro-inflammatory cytokines and chemokines that recruit and activate other immune cells to initiate an adaptive response. From the initial discovery of the diverse cell surface receptors on NK cells to the characterization of regulatory events that control their function, our understanding of the basic biology of NK cells has improved dramatically in the past three decades. This advanced knowledge has revealed increased mechanistic complexity, which has opened the doors to the development of a plethora of exciting new therapeutics that can effectively manipulate and target NK cell functional responses, particularly in cancer patients. Here, we summarize the basic mechanisms that regulate NK cell biology, review a wide variety of drugs, cytokines and antibodies currently being developed and used to stimulate NK cell responses, and outline evolving NK cell adoptive transfer approaches to treat cancer.