Abstract
HOXB13, a homeodomain transcription factor, is linked to recurrence following radical prostatectomy. While HOXB13 regulates Androgen Receptor (AR) functions in a context dependent manner, its critical effectors in prostate cancer (PC) metastasis remain largely unknown. To identify HOXB13 transcriptional targets in metastatic PCs, we performed integrative bioinformatics analysis of differentially expressed genes (DEGs) in the proximity of the human prostate tumor-specific AR binding sites. Unsupervised Principal Component Analysis (PCA) led to a focused core HOXB13 target gene-set referred to as HOTPAM9 (HOXB13 Targets separating Primary And Metastatic PCs). HOTPAM9 comprised 7 mitotic kinase genes overexpressed in metastatic PCs, TRPM8, and the heat shock protein HSPB8, whose levels were significantly lower in metastatic PCs compared to the primary disease. The expression of a two-gene set, CIT and HSPB8 with an overall balanced accuracy of 98.8% and a threshold value of 0.2347, was sufficient to classify metastasis. HSPB8 mRNA expression was significantly increased following HOXB13 depletion in multiple metastatic CRPC models. Increased expression of HSPB8 by the microtubule inhibitor Colchicine or by exogenous means suppressed migration of mCRPC cells. Collectively, our results indicate that HOXB13 promotes metastasis of PCs by coordinated regulation of mitotic kinases and blockade of a putative tumor suppressor gene.
Highlights
The HOX family is an evolutionarily conserved group of gene clusters that code for transcription factors characterized by the presence of homeodomains[11]
To identify HOXB13 transcriptional targets in high-risk metastatic human PCs, we performed integrative bioinformatics analysis of 536 differentially expressed genes (DEGs) in the proximity of the tumor-specific AR binding sites (T-ARBS) enriched for HOXB13/FOXA1 binding motifs[24] (Supplementary Fig. 1a) with the 2677 DEGs that were found to be significantly affected as a result of HOXB13 reduction in the metastatic CRPC cell line, C4-2B/pHOXB13KO (Fig. 1a)[16]
Our present study suggests that HOXB13, a critical regulator of metastatic PC growth[16,34,35], directs a robust pro-proliferative androgen-independent transcriptional program by increasing the expression of a subset of mitotic kinases (Fig. 10: Model)
Summary
The HOX family is an evolutionarily conserved group of gene clusters that code for transcription factors characterized by the presence of homeodomains[11]. To identify the mechanism by which HOXB13 promotes metastasis, we performed integrative bioinformatics analysis to uncover genes that are significantly impacted as a result of HOXB13 depletion in a metastatic PC model cell line and are differentially expressed in human prostate tumors. This integrative analysis approach revealed a previously unknown network of mitotic kinases and a putative tumor suppressor gene whose expression is significantly modulated between primary and metastatic PCs. Collectively, our results indicate that metastasis of prostate cancers is a highly orchestrated event regulated by the transcriptional of activity of the homeobox gene HOXB13
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