Dataset Information

The Homeobox gene, HOXB13, Regulates a Mitotic Protein-Kinase Interaction Network in Metastatic Prostate Cancers.

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.

SUBMITTER: Yao J

PROVIDER: S-EPMC6609629 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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The Homeobox gene, HOXB13, Regulates a Mitotic Protein-Kinase Interaction Network in Metastatic Prostate Cancers.

Yao Jiqiang J Chen Yunyun Y Nguyen Duy T DT Thompson Zachary J ZJ Eroshkin Alexey M AM Nerlakanti Niveditha N Patel Ami K AK Agarwal Neha N Teer Jamie K JK Dhillon Jasreman J Coppola Domenico D Zhang Jingsong J Perera Ranjan R Kim Youngchul Y Mahajan Kiran K

Scientific reports 20190704 1

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. Unsupe ...[more]

PMID: 31273254

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Project description:BackgroundHomeobox B13 (HOXB13) expression regulates normal prostate development and mutations are associated with prostate cancer (PCa) formation.ObjectiveTo assess the role of HOXB13 mRNA expression in PCa progression following radical prostatectomy.Design, setting, and participantsGenome-wide expression profiles were queried from two retrospective prostatectomy cohorts with follow-up data (Mayo Clinic, n=780; Johns Hopkins Medical Institute [JHMI], n=355), and a prospective genomic registry (n=5239).Outcome measurements and statistical analysisMultivariable Cox regressions were used to analyze metastasis-free survival (MFS).Results and limitationsHOXB13 expression in primary PCa increased with increasing tumor grade and with high metastatic potential based on a genomic signature. The highest quartile of HOXB13 expression was associated with worse MFS compared with the lowest quartile (Mayo Clinic: adjusted hazard ratio [AHR] 1.46, 95% confidence interval [CI] 1.03-2.06, and JHMI: AHR 1.80, 95% CI 1.02-3.19). The combinations of high HOXB13 expression and low expression of its binding partner, MEIS1 (AHR 2.03, 95% CI 1.54-2.66) or MEIS2 (AHR 1.73, 95% CI 1.33-2.26), portended worse MFS. Additionally, high HOXB13 expression in combination with low MEIS1/2 expression correlated with high expression of androgen receptor-mediated genes. The retrospective nature of this study subjects the findings to a bias due to unmeasured variables.ConclusionsPrimary PCa tumors with increased HOXB13 expression have an increased propensity for metastases following prostatectomy, particularly in the setting of low MEIS1/2 expression. High androgen receptor output may account for worse outcomes for these tumors and suggests heightened sensitivity to androgen suppression.Patient summaryUsing genomic data from a large number of prostate cancer (PCa) tumors, we found that increased expression of homeobox B13 (HOXB13), a gene related to normal prostate development, was associated with worse outcomes following surgery for PCa. A biomarker signature suggests that these tumors would be more susceptible to androgen suppression, a common treatment for PCa. Take Home Messagece:: In multiple large cohorts, prostate cancer tumors with high homeobox B13 (HOXB13) expression and low expression of its binding partner MEIS1/2 were enriched with high androgen receptor output and had an increased propensity for metastases following surgery.

Dataset Information

The Homeobox gene, HOXB13, Regulates a Mitotic Protein-Kinase Interaction Network in Metastatic Prostate Cancers.

Publications

The Homeobox gene, HOXB13, Regulates a Mitotic Protein-Kinase Interaction Network in Metastatic Prostate Cancers.

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