Downstream of the HOX genes: Explaining conflicting tumour suppressor and oncogenic functions in cancer

Abstract

The HOX genes are a highly conserved group of transcription factors that have key roles in early development, but which are also highly expressed in most cancers. Many studies have found strong associative relationships between the expression of individual HOX genes in tumours and clinical parameters including survival. For the majority of HOX genes, high tumour expression levels seem to be associated with a worse outcome for patients, and in some cases, this has been shown to result from the activation of pro‐oncogenic genes and pathways. However, there are also many studies that indicate a tumour suppressor role for some HOX genes, sometimes with conclusions that contradict earlier work. In this review, we have attempted to clarify the role of HOX genes in cancer by focusing on their downstream targets as identified in studies that provide experimental evidence for their activation or repression. On this basis, the majority of HOX genes would appear to have a pro‐oncogenic function, with the notable exception of HOXD10, which acts exclusively as a tumour suppressor. HOX proteins regulate a wide range of target genes involved in metastasis, cell death, proliferation and angiogenesis, and activate key cell signalling pathways. Furthermore, for some functionally related targets, this regulation is achieved by a relatively small subgroup of HOX genes.

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“…Interestingly, for a subset of these hypermethylated genes methylation positively correlated with gene expression. Many of these hypermethylated, upregulated genes belonged to the family of developmental transcription factors [57] and have been previously implicated in breast cancer etiology and the development of endocrine resistance [58], including GATA2 [59], HOXC4 [60], HOXB13 [61], HOXC13 [62], MNX1 [63], OTX1 [64], PAX7 , SOX2 [65] and WT1 [66]. Notably, one of the 12 AI DMSs associated with HOXC4 was included in both AI models.…”