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 the Hox proteins interact with ERK oncogenicity. Using an in vivo neoplasia model in the chicken embryo consisting in the overactivation of the ERK1/2 kinases in the trunk neural tube, we analyzed the consequences of the HOXB8 gain of function at the morphological and transcriptional levels. We found that HOXB8 acts as a tumor suppressor, counteracting ERK-induced neoplasia. The HOXB8 tumor suppressor function relies on a large reversion of the oncogenic transcriptome induced by ERK. In addition to showing that the 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.
Highlights
The HOX family is an evolutionary conserved set of proteins that regulate developmental processes such as anteroposterior body axis patterning, organ morphogenesis and cell fate
To gain insights in the molecular mechanisms by which the HOX proteins control ERK oncogenic pathways, we developed a chicken embryo neoplasia model obtained by ERK1/2 overactivation in the trunk neural tube [27] and investigated the effects of HOX expression in this model
We have demonstrated that the gain of function of HOXB8 in the trunk neural tube of a 2-day-old chicken embryo performed by electroporation of the pCIG-HOXB8 expressing vector increases cell death and the amount of the transcript of the gene coding for the tumor suppressor LZTS1 [12]
Summary
The HOX family is an evolutionary conserved set of proteins that regulate developmental processes such as anteroposterior body axis patterning, organ morphogenesis and cell fate. As transcription factors, their mainly act by target gene transcriptional activation or repression [1,2]. HOX genes are numbered 1 through 13 so that each HOX has up to four paralogs on each of the four chromosomal loci. Their role in embryonic development during which their spatial and temporal expression is tightly governed is well established [2]. HOX genes remain expressed in adult tissues and participate, among other things, in tissue-specific stem cell differentiation contributing to the maintenance and function of various organs and tissues [4]
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