Resetting cancer stem cell regulatory nodes upon MYC inhibition. (16th November 2016) - Galardi, Silvia
Abstract: MYC deregulation is common in human cancer and has a role in sustaining the aggressive cancer stem cell populations. MYC mediates a broad transcriptional response controlling normal biological programmes, but its activity is not clearly understood. We address MYC function in cancer stem cells through the inducible expression of Omomyc—a MYC‐derived polypeptide interfering with MYC activity—taking as model the most lethal brain tumour, glioblastoma. Omomyc bridles the key cancer stemlike cell features and affects the tumour microenvironment, inhibiting angiogenesis. This occurs because Omomyc interferes with proper MYC localization and itself associates with the genome, with a preference for sites occupied by MYC. This is accompanied by selective repression of master transcription factors for glioblastoma stemlike cell identity such as OLIG2, POU3F2, SOX2, upregulation of effectors of tumour suppression and differentiation such as ID4, MIAT, PTEN, and modulation of the expression of microRNAs that target molecules implicated in glioblastoma growth and invasion such as EGFR and ZEB1. Data support a novel view of MYC as a network stabilizer that strengthens the regulatory nodes of gene expression networks controlling cell phenotype and highlight Omomyc as model molecule for targeting cancer stem cells. Synopsis: Cancer stemlike cells are key to cancer development and therapy. The MYC‐interfering polypeptide, Omomyc, impairs the carcinogenic potential of human glioblastoma stemlike cells (GSCs) and affects proper MYC genomic localization. This indicates that the gene regulatory nodes determining GSC identity are MYC dependent. Omomyc occupies DNA E‐boxes targeted by MYC network complexes, weakening the gene expression programme control nodes and facilitating phenotype changes in the presence of appropriate stimuli. Expression of Omomyc in GSCs— in vitro and in xenografts—rebalances their transcriptome towards differentiation and tumour suppression by affecting the transcript levels of master transcription factors and key non‐coding RNAs. Blunting MYC activity by Omomyc restrains GSC tumorigenic features—self‐renewal, proliferation, differentiation, migration and tumour vascularization— in vitro and in vivo by both cell‐autonomous and non‐cell‐autonomous mechanisms. Abstract : Cancer stemlike cells are key to cancer development and therapy. The MYC‐interfering polypeptide, Omomyc, impairs the carcinogenic potential of human glioblastoma stemlike cells (GSCs) and affects proper MYC genomic localization. This indicates that the gene regulatory nodes determining GSC identity are MYC dependent.