Oncogene. 2025 Aug 4. doi: 10.1038/s41388-025-03523-9. Online ahead of print.
ABSTRACT
Medulloblastomas are the most common solid paediatric cancers. Their prognosis largely depends on tumour subtype and expression level of transcription factor such as Orthodenticle homeobox 2 (OTX2). OTX2 is an homeoprotein that maintains stemness and initiates oncogenic pathways. Additionally, as many other homeoproteins, OTX2 is able to travel between cells and to modify the transcriptional activity of recipient ones. After identifying travelling proteins in in vivo models, a systematic review of the literature highlighted that at least eleven travelling homeoproteins are associated with medulloblastoma: Cut like homeobox 1 (CUX1), Engrailed homeobox 1 and 2 (EN1 and EN2), Insulin gene enhancer protein ISL-1 (ISL1), LIM homeobox 1 (LHX1), Homeobox protein Nkx-2.2 (NKX2.2), OTX2, Paired box protein Pax-5,6 and 8 (PAX5, PAX6 and PAX8), as well as POU domain, class 5, transcription factor 1 (POU5F1). Overexpression of some of these homeoprotein-coding gene including OTX2 and POU5F1 was found to be associated with poor prognosis, while overexpression of PAX8 seems to have a protective effect, with a significantly better overall and progression-free survival. Research efforts to better understand the transfer mechanisms and intracellular targets of these transcription factors may offer a new range of therapeutics tools, by interfering with these roaming oncoproteins to circumscribe their associated chain reaction of genetic deregulation, or by providing protective homeoprotein supplementation with the aim of stemming tumour development by direct cancer cell penetration and reprograming.
PMID:40760093 | DOI:10.1038/s41388-025-03523-9
