Abstract
Collagen prolyl hydroxylases (C-P4HAs) are a family of enzymes involved in collagen biogenesis. One of the isoforms of P4HA, Prolyl 4-hydroxylase, alpha polypeptide I (P4HA1), catalyzes the formation of 4-hydroxyproline that is essential for the proper three-dimensional folding of newly synthesized procollagen chains. Here, we show the overexpression of P4HA1 in aggressive prostate cancer. Immunohistochemical analysis using tissue microarray demonstrated that P4HA1 expression was correlated with prostate cancer progression. Using in vitro studies, we showed that P4HA1 plays a critical role in prostate cancer cell growth and tumor progression. Expression profiling studies using P4HA1 modulated prostate cells suggested regulation of Matrix metalloproteases 1. The invasive properties of P4HA1 overexpressing cells were reversed by blocking MMP1. Our studies indicate P4HA1 copy number gain in a subset of metastatic prostate tumors and its expression is also regulated by microRNA-124. MiR-124 in turn is negatively regulated by transcriptional repressors EZH2 and CtBP1, both of which are overexpressed in aggressive prostate cancer. Chick chorioallantoic membrane (CAM) assay and mice xenograft investigations show that P4HA1 is required for tumor growth and metastasis in vivo. Our observations suggest that P4HA1 plays a critical role in prostate cancer progression and could serve as a viable therapeutic target.
Highlights
Prostate cancer is the most common malignancy and the second most common cause of cancer death among men in the United States [1]
We investigated the expression of P4HA1 protein in large number of prostate cancer samples by immunohistochemical (IHC) analysis that showed weak or no reactivity in benign tissues but strong staining in the aggressive prostate cancer tissue and metastatic prostate tumors (Figure 1D)
Our study showed that P4HA1 serves as a progression marker and potential enzymatic therapeutic target
Summary
Prostate cancer is the most common malignancy and the second most common cause of cancer death among men in the United States [1]. While multiple molecular events characterize prostate cancer initiation, growth, invasion, and metastasis, the exact mechanism of tumorigenesis remains unclear. Identification of oncogenic drivers and potential therapeutic targets is critical for both early diagnosis and effective treatment. Gene expression profiling studies and high throughput transcriptome sequence analyses have revealed tumorspecific gene signatures and multiple oncogenic drivers [2-. We characterized prolyl 4-hydroxylase, alpha polypeptide I (P4HA1) as overexpressed in aggressive prostate cancer. P4HA1 is a key enzyme in collagen biogenesis. The proper triple helical collagen formation involves extensive post-translational modifications including hydroxylation of prolyl and lysyl residues [11, 12]. P4HA1 catalyzes the formation of 4-hydroxyproline that is essential for the proper threedimensional folding of newly synthesized procollagen chains
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