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HOX genes: HOX transcription factors as biomarkers in cancer

19 October 2011  •  Author(s): Richard Morgan, Postgraduate Medical School, Faculty of Health and Medical Sciences, University of Surrey

The HOX genes are a family of closely related transcription factors that help to define the identity of cells and tissues during embryonic development and which are also frequently deregulated in cancer, where they have been shown to promote cell survival and proliferation. The high level of cancer-associated HOX expression and the pro-oncogenic functions of these genes make them strong candidates for biomarkers in multiple roles including diagnosis, prognosis, drug sensitivity and drug resistance.

The HOX genes are a family of homeodomaincontaining transcription factors that were first identified as determinates of cell and tissue identity in early development, although they are now also known to function in adult stem cell renewal and differentiation1. A series of duplication events is thought to have given rise to the four separate clusters of HOX genes found in vertebrates, with each cluster consisting of a group of closely linked members that often share enhancer regions. These clusters are named A, B, C and D, and together they contain the 39 HOX genes found in mammals2. Each gene within a cluster is labelled with a number according to their relative position in the chromosome, so for example HOXB1 is the 3’ most member of the B cluster, and HOXB13 is the 5’ most member3. The linkage of genes within each cluster is closely reflected in both their temporal and spatial order of expression in the embryo, with the 3’ genes being expressed more anteriorly and earlier than their 5’ neighbours (Figure 1). The relative position within the cluster is also reflected in the co-factor interactions, DNA binding specificity and regulation of each member2.

HOX genes also deregulated in a number of cancers

In addition to a role in development, and subsequently in stem cell differentiation, the HOX genes are also frequently deregulated in a number of cancers including melanoma, mesothelioma, and lung, kidney, prostate, ovarian and breast cancer4. Their function in oncogenesis is still unclear; however, it is apparent that the great complexity of HOX function in development is also reflected in oncogenesis, with some HOX genes functioning as tumour suppressors and others as oncogenes. The best known examples of both have been identified in breast cancer, where HOXA5 is known to function as a tumour suppressor5, at least in part through activating the transcription of the key tumour suppressor gene TP536. Conversely, members of the closely related HOXB genes including HOXB5 and HOXB7 are oncogenic through mechanisms which include an up regulation of FGF27, and the promotion of epithelial to mesenchymal transition8. Exactly how such similar transcription factors can have opposing functions is also unclear, although it may be related to differential co-factor binding and consequently differential regulation of target genes. Known co-factors include members of the PBX, MEIS and PREP families of transcription factors, all of which can influence the binding selectivity of HOX proteins and their action as either a suppressor or activator of transcription1. As an additional complexity, HOX proteins can also regulate transcription through binding to DNA as monomers9.

Whilst different HOX genes can have individual, specific functions in embryonic development, there is generally a high level of functional redundancy, especially with regards to fundamental and highly conserved patterning events such as anterior-posterior pattering of the spine and hindbrain10,11. This is also true in cancer, where a similar oncogenic function is common to a number of HOX genes, especially HOXB1 through to HOXB911,12. The highly complex expression of HOX genes in different cancers gives rise to the possibility of a ‘fingerprint’ that can be used to distinguish different types of cancer, and also to potentially diagnose cancer based on the presence of specific HOX proteins in cells or in bodily fluids. Furthermore, the diverse range of functions that HOX genes have in cancer also raises the possibility of using them as prognostic markers and / or predictive markers for the response to treatment. As yet this is an under-explored area of research, but here I have reviewed some of the key findings to date that illustrate the potential of HOX genes as biomarkers in cancer.

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