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Morgan et al. HOX genes and the tumor microenvironment

The most extensively studied HOX gene in prostate androgen-stimulated cell proliferation , and has also
[49]
cancer is HOXB13 due to its apparent role in androgen been shown to bind directly to the enhancer region
sensitivity. It has been shown to be highly expressed of the RFX6 gene, the product of which inhibits the
in androgen receptor (AR) positive prostate cancer- proliferation, migration, and invasion of prostate cancer
derived cell lines, but only at a very low level in AR cells . HOXB13 additionally represses prostate
[50]
negative cell lines [42,43] , and to be strongly expressed derived Ets factor (PDEF) expression, which in turn
in hormone-refractory tumors after initial treatment . blocks the expression of matrix metalloproteinase
[44]
Furthermore, mutations in HOXB13 are associated 9 (MMP-9) and the anti-apoptotic protein survivin,
with an increased risk of prostate cancer. The G84E and thus reduces the invasive potential of cells . A
[51]
variant was found to significantly increase the risk further pro-oncogenic effect of HOXB13 is exerted
of heredity prostate cancer , and was present in through the upregulation of zinc transporters that in
[45]
around 5% of families with at least one affected turn results in lower intracellular zinc concentrations.
member . A second variant, G135E was found to be This reduces the level of inhibitor of NF-κΒ alpha
[46]
associated with an increased risk of prostate cancer (IκΒα) and promotes NF-κΒα signaling leading to
in Chinese men . At the cellular level the functional increased invasion and metastasis . Thus, HOXB13
[52]
[47]
significance of these variants remains unclear; for exerts multiple tumor-promoting effects through the
example, HOXB13 G84E was not found to result in regulation of specific target genes.
an appreciably different phenotype to the wild type
gene when expressed in PNT2 cells . However, a In addition to their roles in regulating the proliferation
[48]
clear mechanistic basis for the pro-oncogenic role of and survival of prostate cancer cells, it has become
HOXB13 has arisen over the last few years [Figure 1]. apparent that the HOX genes are also instrumental
HOXB13 protein can function both as a repressor and in promoting changes to the tumor microenvironment
activator of transcription. It represses the p21WAF1/ that support metastasis and angiogenesis [Figure 2].
CIP1 (p21) tumor suppressor gene, which can block Each of these aspects will be considered in detail in

Figure 1: HOXB13 exerts multiple tumor-promoting effects through the regulation of specific target genes. HOXB13 protein can function
both as a repressor and activator of transcription. It represses the p21WAF1/CIP1 (p21) tumor suppressor gene, which can block androgen-
stimulated cell proliferation and has also been shown to bind directly to the enhancer region of the RFX6 gene, the product of which inhibits
the proliferation, migration, and invasion of prostate cancer cells. HOXB13 additionally represses prostate derived Ets factor (PDEF)
expression, which in turn blocks the expression of matrix metalloproteinase 9 (MMP-9) and the anti-apoptotic protein survivin, and thus
reduces the invasive potential of cells. A further pro-oncogenic effect of HOXB13 is exerted through the upregulation of zinc transporters
resulting in lower intracellular zinc concentrations. This reduces the level of inhibitor of NF-κB alpha (IκBα) and promotes NF-κBα signaling
leading to increased invasion and metastasis. Right pointing arrows in the nucleus indicate transcription. AR: androgen receptor
280 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ December 6, 2017