Comprehensive Analyses of HOXB13-regulated Transcriptional programs critical for Prostate Cancer Progression

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Summary Prostate cancer (PCa) is the most commonly diagnosed non-skin cancer in American men. Early-stage PCa can be effectively ablated with surgery and/or radiation treatments. However, metastatic PCa remains a challenge, and the standard treatment is androgen-deprivation therapy (ADT). However, a majority of PCa patients develop resistance to ADT over a period of months to years, ultimately resulting in castration-resistant PCa (CRPC) and widespread aggressive tumors. The mechanisms for this resistance are not fully understood, but it has been shown that aggressive PCa tumors accumulate lipid droplets for fueling metastatic progression. Thus, a key to overcoming ADT is to identify the driver genes of tumor metastasis, such as lipogenesis genes, which may be promising targets for therapeutic intervention and a long-term cure. In preliminary studies, we found that HOXB13, a prostate-specific homeodomain-containing transcription factor, is down-regulated in CRPC as compared to primary PCa, and we found a previously uncharacterized role of HOXB13 in transcriptional repression of lipogenesis. We identify a novel HOXB13-interacting protein, the histone deacetylase 3 (HDAC3), which closes target chromatin for gene repression. Of note, this interaction is disrupted by HOXB13 G84E mutation that has been reported in familial PCa and associated with early-onset PCa. Moreover, our data showed that HDAC3-regulated genes remarkably overlapped with HOXB13-regulated genes. Like HOXB13, HDAC3 inhibits lipogenic genes, such as fatty acid synthase (FASN), and this is accompanied by the removal of acetylation on key histones at target genes. Hence, our central hypothesis is that HOXB13 recruits HDAC3 to repress lipogenic gene expression through epigenetic remodeling and that FASN inhibitors (FASNi) will be effective in treating CRPC with low or G84E-mutant HOXB13. To test these hypotheses, Aim 1 will examine the molecular mechanisms by which HOXB13 interacts and recruits HDAC3 protein to target chromatin to catalyze histone de-acetylation and repress lipogenic gene expression. We will also investigate how this HOXB13/HDAC3-mediated lipogenic program cross talks with AR, which plays a major role in inducing lipid metabolism, and identify key downstream mediators in addition to FASN. Aim 2 will examine the protein levels of HOXB13 and its key target genes in human CRPC specimens, determine how HOXB13 and its G84E mutant regulate prostate tumorigenesis using diverse PCa models, and evaluate the efficacy of FASNi on prostate tumor growth and metastasis using HOXB13-low or -high xenograft and PDX models.