HOXB13 regulates the prostate-derived Ets factor: Implications for prostate cancer cell invasion

Abstract

HOXB13 has been shown to enhance the invasive potential of breast and endometrial tumors. HOXB13 is also abundant in castration-resistant prostate tumors. To determine the invasive potential of HOXB13 in prostate tumors, highly metastatic PC3 prostate cancer cells were manipulated to express HOXB13 and/or the prostate-derived Ets factor (PDEF). The PDEF is believed to reduce the invasive potential of various tumors, including prostate tumors. To further demonstrate the functional correlation between HOXB13 and PDEF, transwell invasion and gelatin zymography assays were performed. In addition, the western blot analysis was used to demonstrate the expression of PDEF target proteins involved in cancer cell migration and invasion, MMP-9 and survivin. According to the results, HOXB13 promoted PC3 cell migration and invasion. The DNA microarray analysis demonstrated that HOXB13 significantly suppressed the expression of the PDEF. Accordingly, the expression of MMP-9 and survivin was regulated by HOXB13. In addition, HOXB13 promoted the invasive potential of PC3 cells while inhibiting the PDEF. The coexpression of HOXB13 and the PDEF led to moderate retardation of the number of invasive cells, indicating that HOXB13 functionally counteracted cell invasion by reducing PDEF expression. The western blot analysis demonstrated that HOXB13 counteracted the PDEF-mediated inhibition of the expression of PDEF target proteins such as MMP-9 and survivin. The results suggest that the HOXB13-mediated promotion of tumor cell invasion is accomplished mainly through the downregulation of PDEF expression.

Paralogous HOX13 Genes in Human Cancers

“…Combined analyses of HOXB13 and PSA, in metastatic PCs, shows that only HOXB13 is able to distinguish metastatic PCs with high sensitivity and specificity [92]. HOXB13 is able to interact with different molecular pathways during PC evolution: (i) suppresses Prostate Derived ETS Factor (PDEF) [93]; (ii) suppresses p21 in castration-resistant PC, stressing this important step in PC cell survival under no androgen-influence [94]; (iii) promotes PC cell invasion and metastasis by decreasing intracellular zinc levels, enhancing NF-kB [95]. Moreover, a direct biochemical and functional interaction has been described between HOXB13 and MEIS1 in PC cells: the corresponding two proteins are co-expressed on PC tissues with the consequence of modulating PC tumor progression by prolonging HOXB13 half-life [96].…”

Prostate-Derived Ets Factor (PDEF) Inhibits Metastasis by Inducing Epithelial/Luminal Phenotype in Prostate Cancer Cells

“…In the context of metastatic prostate cancer, PDEF inhibits Slug and MMPs levels (19,22). Furthermore, oncogenes such as HOXB13 and CDK11p58 suppress PDEF expression (23,24).…”

MEIS-mediated suppression of human prostate cancer growth and metastasis through HOXB13-dependent regulation of proteoglycans

“…HOXB13 has critical roles in normal prostate secretory function, differentiation, and response to androgens in rodent prostate models and is implicated in human PrCa ( Chen et al, 2018 ; Economides and Capecchi, 2003 ; Hamid et al, 2014 ; Huang et al, 2007 ; Jung et al, 2004a ; Jung et al, 2004b ; Kim et al, 2014a ; Kim et al, 2010a ; Kim et al, 2014b ; Kim et al, 2010b ; Navarro and Goldstein, 2018 ; Pomerantz et al, 2015 ). Comparative analyses of HOX gene mRNA expression using publicly-available RNA-Seq datasets of adult human prostate tissues demonstrated that HOXB13 is the highest-expressed ( Pflueger et al, 2011 ; Robinson et al, 2015 ) HOX gene across benign epithelium, tumor, and metastatic tissue; HOXA10 is the next-highest (FPKMs HOXB13 vs. HOXA10: benign, 167.69 vs 38.53; primary tumor, 197.40 vs 35.63; metastasis, 149.44 vs 28.03, Figure 2A ; Bhanvadia et al, 2018 ).…”