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Morgan et al. HOX genes and the tumor microenvironment

mutations in either their reading frame or regulatory include the menstrual cycle and the differentiation
[17]
regions, and one of the most notable examples of of mesenchymal stem cells . Over the last 20 years
[18]
this are the HOX genes . The HOX genes encode it has become increasing clear that HOX genes are
[5]
transcription factors that are characterized at the also very highly dysregulated, and usually strongly
protein level by a highly conserved DNA-binding over expressed in a wide range of haematological
domain, known as the homeodomain, and their and solid malignancies compared to the cells form
expression defines the identity of cells primarily along which these cancers originate [19,20] . The HOX genes
the anterior to posterior axis of the embryo, both in have multiple functions in cancer, and can act both as
the main body and within organs and appendages . tumor suppressors and oncogenes. Examples of the
[6]
Mammals have 39 HOX genes that are organized former include HOXA5, which can promote expression
in 4 distinct chromosomal clusters named A, B, C, of the p53 tumor suppressor protein , and HOXC12,
[21]
and D. The HOX genes are named on the basis of which promotes cellular differentiation in follicular
which cluster they are found in, and their position lymphoma . However, the majority of reports indicate
[22]
within the cluster. Thus for example HOXB1 is the 3’ that HOX genes have a pro-oncogenic role, including
most member of the HOXB cluster, and its immediate functions that support tumor growth and invasion such
5’ neighbor is consequently named HOXB2 . as angiogenesis, metastasis, and immune evasion .
[7]
[23]
The clusters arose through multiple duplication At the cellular level, a generalized role for many HOX
events during the evolution of vertebrates, and proteins in cancer appears to be to prevent apoptosis
consequently HOX genes at equivalent positions by inhibiting cFos [24-27] and dual specificity protease
within each cluster (e.g. HOXA1, HOXB1, HOXC1, 1 (DUSP1) expression [26,28,29] . DUSP1 is a tumour
[30]
and HOXD1) share high levels of sequence identity suppressor gene , and whilst cFos is generally
beyond the conserved homeodomain region, and are considered to be a protoncogene, cFos protein can
referred to as paralogues . The sharing of enhancer also induce apoptosis through the activation of the cell
[5]
regions within clusters confers unusual regulatory death ligand, FAS1 [31-35] . Additional cellular functions
[36]
properties on HOX genes, whereby the 3’ members of individual HOX proteins include DNA repair and
[37]
are expressed earlier in development (temporal the regulation of the cell cycle . It has also become
collinearity) and more anteriorly (spatial collinearity) apparent that the HOX genes function to modify the
than their 5’ neighbors . tumour microenvironment, and it is this aspect of their
[8]
biology that we focus on here.
HOX proteins can bind as monomers to DNA,
although the affinity and specificity of binding are HOX GENES IN PROSTATE CANCER
considerably increased through an interaction with
other homeodomain-containing transcription factors The role of HOX genes in prostate cancer has in
including Pre-B-cell Leukemia Homeobox (PBX) and general been more extensively studied than for other
Myeloid Ecotropic Viral Integration Site 1 Homolog solid malignancies. HOXC4, HOXC5, HOXC6, and
(MEIS) proteins . Of these, PBX can bind to HOX HOXC8 have all been found to be highly expressed in
[9]
proteins from paralogue groups 1-11 [10-12] , whilst MEIS lymph node metastases , and HOXC6 and HOXC8
[38]
binds to HOX9-13 proteins . Despite this increased overexpression has also been demonstrated in
[13]
binding specificity, HOX proteins exhibit high levels primary tumors . HOXC8 expression was also shown
[25]
of functional redundancy in some contexts due to to be higher in tumors with a higher Gleason score .
[39]
extensive sequence identity between paralogue group Of these 4 HOX genes, HOXC6 is reported to be the
members and 3’ and 5’ neighbors . most highly upregulated in primary, metastasized, and
[14]
castrate-resistant prostate cancer, and the presence
HOX gene expression generally reduces before of HOXC6 RNA in urine might be a diagnostic marker
birth and many adult cells show either low levels of for prostate cancer and a potential monitoring tool for
expression, or no expression. Exceptions include cells disease progression , and was shown to distinguish
[40]
that maintain proliferative capacity in the adult, for between high and low grade prostate tumors with a
example stem cells, and most notably hematopoietic very high specificity when used in conjugation with a
stem cells (HSCs), which are dependent on the second urinary marker, DLX1 . In addition, disrupting
[41]
continued expression of HOXB4 for proliferation . the interaction between HOX proteins and their PBX
[15]
The subsequent differentiation of HSCs along cofactor using the competitive antagonist HXR9
[23]
different lineages and ultimately to mature blood causes apoptotic cell death in the prostate cancer-
cells is also dependent on distinct patterns of HOX derived cell lines LnCaP, DU145, and PC3, and was
gene expression . Other adult processes that are shown to block the growth of PC3 tumors in a mouse
[16]
known to be at least partly dependent on HOX genes xenograft model .
[25]
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 6, 2017 279