HOXB13 suppresses a lipogenic transcriptional program in prostate cancer (PCa) through
HDAC3 recruitment to enhancers. Loss of HOXB13 leads to lipid accumulation in PCa
cells, promoting cell motility in vitro and xenograft tumor metastasis in vivo.HOXB13,
a homeodomain transcription factor, critically regulates androgen receptor (AR) activities
and androgen-dependent prostate cancer (PCa) growth. However, its functions in AR-independent
contexts remain elusive. Here we report HOXB13 interaction with histone deacetylase
HDAC3, which is disrupted by the HOXB13 G84E mutation that has been associated with
early-onset PCa. Independently of AR, HOXB13 recruits HDAC3 to lipogenic enhancers
to catalyze histone deacetylation and suppress lipogenic regulators such as fatty
acid synthase. Analysis of human tissues reveals that the HOXB13 gene is hypermethylated
and downregulated in approximately 30% of metastatic castration-resistant PCa. HOXB13
loss or G84E mutation leads to lipid accumulation in PCa cells, thereby promoting
cell motility and xenograft tumor metastasis, which is mitigated by pharmaceutical
inhibition of fatty acid synthase. In summary, we present evidence that HOXB13 recruits
HDAC3 to suppress de novo lipogenesis and inhibit tumor metastasis and that lipogenic
pathway inhibitors may be useful to treat HOXB13-low PCa.
