Human PARM‐1 is a novel mucin‐like, androgen‐regulated gene exhibiting proliferative effects in prostate cancer cells

Abstract

In this paper we characterize hPARM-1, the human ortholog of rat PARM-1 (prostatic androgen-repressed message-1) and demonstrate its role in prostate cancer. Immunofluorescence microscopy and ultrastructural analysis revealed the localization of hPARM-1 to Golgi, plasma membrane and the early endocytic pathway but not in lysosomes. Biochemical and deglycosylation studies showed hPARM-1 as a highly glycosylated, mucin-like type I transmembrane protein. Analysis of expression of hPARM-1 in various human tissues revealed its presence in most human tissues with especially high expression in heart, kidney and placenta. Androgen controls the expression of the gene as a marked 7-fold increase is seen in the androgen-dependent prostate cancer cell line, LNCaP on androgen stimulation. This is further supported by its decrease in expression in CWR22 xenograft upon castration. Moreover, ectopic expression of hPARM-1 in PC3 prostate cancer cells increased colony formation, suggesting a probable role in cell proliferation. These results suggest that hPARM-1 may have a role in normal biology of the prostate cell and in prostate cancer. ' 2007 Wiley-Liss, Inc.

Characterization and identification of PARM-1 as a new potential oncogene

“…mPARM-1 sequence contains 3 N-glycosylated motifs and 65 mucin-type O-glycosylated sites [16], suggesting that, as its human counterpart, mPARM-1 should be highly glycosylated. Moreover, we found that 41% of the amino acid composition of mPARM-1 is represented by serine, proline and threonine residues similar to the human protein [17]. Interestingly, amino acid sequence alignment of PARM-1 homologs showed that the C-terminus is highly conserved (Additional file 1: Figure S1) suggesting an important role through evolution.…”

“…We were interested to confirm that hPARM-1 protein is localized to the Golgi, at the early endocytic pathway and at the plasma membrane [17] and investigated the localization of the murine protein in NIH/3T3 cells. Both mPARM-1-GFP or hPARM-1-GFP proteins were localized at the Golgi and have punctate and typical endosomal localization (Figure 4a).…”

“…Indeed, the rat Parm-1 is over-expressed in prostate epithelial cells after androgen deprivation following castration [26]. However, its human counterpart expression is increased by androgen in the LNCaP prostate cancer cell line and decreased in the CWR22 xenograft upon castration [17]. Moreover, ectopic expression of hParm-1 in human prostate cancer cell line enhances their proliferation [17].…”

Generation of Mice Deficient in both KLF3/BKLF and KLF8 Reveals a Genetic Interaction and a Role for These Factors in Embryonic Globin Gene Silencing

“…S5 in the supplemental material). Notably, several of these genes, including Itgb7 (78), Vegfa (79,80), Periostin (81), Parm1 (82,83), Gbp1 (84,85), Tcfl5 (86,87), Rps3a (88), and Fpr1 (89,90), are regulators of cell adherence, migration, and invasiveness, consistent with the role of KLF8 in oncogenesis. In addition, the Klf8 gene itself is significantly downregulated in Klf3 Ϫ/Ϫ Klf8 gt/gt compared to Klf3 Ϫ/Ϫ cells, as anticipated ( Fig.…”

Meta-analysis of Gene Expression Data Identifies Causal Genes for Prostate Cancer

“…Previous studies have reported that PARM-1 is a novel mucin-like, androgen-regulated gene exhibiting proliferative effects in prostate cancer cells (Fladeby et al, 2008), and it may play a role in prostatic cell immortalization (Cornet et al, 2003). The MYLK gene was also presented significant changes in functional connectivity between normal and tumoral conditions of prostates (Fujita et al, 2008).…”