Asunto(s)
Investigación Biomédica/economía , Investigación Biomédica/tendencias , Organizaciones de Beneficencia/economía , Objetivos , Neoplasias , Erradicación de la Enfermedad , Sistemas de Liberación de Medicamentos , Infecciones por Virus de Epstein-Barr/complicaciones , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Neoplasias/virología , Proteína Oncogénica p55(v-myc)/antagonistas & inhibidores , Farmacogenética , Apoyo a la Investigación como Asunto/economía , Apoyo a la Investigación como Asunto/tendencias , Reino UnidoRESUMEN
MYC family oncoproteins (MYC, NMYC and LMYC) function as basic helixloophelixleucine zipper (bHLHZip) transcription factors that are activated (i.e., overexpressed) in well over half of all human malignancies (Boxer & Dang, 2001; Beroukhim et al, 2010). In this issue of EMBO Molecular Medicine, Eilers and colleagues (Peter et al, 2014) describe a novel approach to disable MYC, whereby inhibition of the ubiquitin ligase HUWE1 stabilizes MIZ1 and leads to the selective repression of MYCactivated target genes.
Asunto(s)
Neoplasias Colorrectales/enzimología , Proteína Oncogénica p55(v-myc)/antagonistas & inhibidores , Proteína Oncogénica p55(v-myc)/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Animales , HumanosRESUMEN
Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high-throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.