HOXB8 counteracts MAPK/ERK oncogenic signaling in a chicken embryo model of neoplasia

Abstract

HOX transcription factors are members of an evolutionarily conserved family of proteins required for the establishment of the anteroposterior body axis during bilaterian development. Although they are often deregulated in cancers, the molecular mechanisms by which they act as oncogenes or tumor suppressor genes are only partially understood. Since the MAPK/ERK signaling pathway is deregulated in most cancers, we aimed at apprehending if and how Hox proteins interact with ERK oncogenicity. Using an in vivo neoplasia model in the chicken embryo that we have developed, consisting in the overactivation of the ERK1/2 kinases in the trunk neural tube, we analyzed the consequences of HOXB8 gain of function at morphological and transcriptional level in this model. We found that HOXB8 acts as a tumor suppressor, counteracting ERK-induced neoplasia. HOXB8 tumor suppressor function in this model relies on a large reversion of the oncogenic transcriptome induced by ERK. In addition to showing that HOXB8 protein controls the transcriptional responsiveness to ERK oncogenic signaling, our study identified new downstream targets of ERK oncogenic activation in an in vivo context that could provide clues for therapeutic strategies.