Comprehensive analyses of HOXB13-regulated transcriptional programs critical for prostate cancer progression

Project: Research project

Project Details

Description

Metastatic castration-resistant prostate cancer (CRPC) is a major cause of prostate cancer (PCa)-associated mortality. Genes/proteins that drive or sustain CRPC tumor growth and metastasis are promising targets for therapeutic intervention. HOXB13 is a transcription factor that is required for prostate development and is highly expressed in adult prostate tissues, in particular, suggesting an important role in normal prostate function. In our preliminary studies, we found that HOXB13 is drastically down-regulated in CRPC as compared to primary PCa. Along this line, germline mutation of HOXB13, namely G84E mutation, has been reported in familial PCa and is associated with early onset disease. And yet, there are only a handful of studies of HOXB13 to date as a cofactor of androgen receptor (AR) and its role beyond this context has not been examined.
In preliminary studies, we found a novel role of HOXB13 in suppressing lipid metabolism, a function that is disrupted by G84E mutation. Mechanistically, this may be due to HOXB13 interaction with the histone deacetylase HDAC3. Our data suggest that HOXB13 may be able to recruit HDAC3 protein to target genes to remove histone acetylation, thereby leading to gene repression. Many of these target genes, including FASN, a fatty acid synthase, are involved in lipid biosynthesis and steroid metabolism. Functionally, down-regulation of HOXB13 leads to FASN expression and lipid accumulation, which has been shown to induce cell invasiveness and tumor metastasis. Our long-term objective is to investigate the molecular mechanisms by which HOXB13 regulates CRPC progression and to develop novel therapeutic approaches. Our central hypothesis is that HOXB13 recruits HDAC3 to repress lipogenic programs through epigenetic remodeling and that FASN inhibitors will be effective in treating CRPC with low or G84E-mutant HOXB13.
To test these hypotheses, in Aim 1 we will examine the molecular mechanisms by which HOXB13 interacts with the HDAC3 protein and recruits it to target genes to catalyze histone de-acetylation and repress gene expression. We will also identify key downstream genes that mediate this novel role of HOXB13. Aim 2 will first examine the protein levels of HOXB13 and its key target genes in human CRPC specimens. We will then characterize the roles of HOXB13 wildtype and G84E mutant in regulating prostate tumorigenesis using diverse PCa cell line and mouse models. We will also perform preclinical studies of TVB-3166, a novel, highly potent, orally available, selective FASN inhibitor in abolishing HOXB13 loss-induced oncogenesis.
StatusActive
Effective start/end date3/4/212/28/26

Funding

  • National Cancer Institute (1R01CA257446-01)

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