ZNF185, an actin–cytoskeleton-associated growth inhibitory LIM protein in prostate cancer

Abstract

We have recently identified ZNF185 as a gene that is downregulated in prostate cancer (PCa), in part via epigenetic alteration, and maybe associated with disease progression. In this study, we cloned the ZNF185 cDNA from normal human prostate tissues and investigated its biological function. We show that ZNF185 is a novel actin-cytoskeleton-associated Lin-l 1, Isl-1 and Mec-3 (LIM) domain-containing protein that localizes to F-actin structures, and is enriched at focal adhesions. We find that the NH 2 -terminal region, which we designate the actintargeting domain, facilitates ZNF185 binding to actin in vitro and is both necessary and sufficient to mediate actin-cytoskeleton targeting of ZNF185, whereas the LIM domain, which is localized in the COOH-terminus is dispensable for this phenomenon. Interestingly, ectopic expression of full-length ZNF185, but not a mutant lacking the actin-targeting domain, could suppress proliferation and anchorage-independent growth of PCa cells. Together, our data suggest that ZNF185 may function as a tumor-suppressor protein by associating with the actincytoskeleton.

Differential gene expression in the peripheral zone compared to the transition zone of the human prostate gland

“…17 Recent studies suggest that ZNF185 may function as a tumour-suppressor protein by associating with the actin cytoskeleton through its N-terminal region. 18 Our findings suggest that ZNF185 overexpression may be an important block to CaP progression in the PZ and its epigenetic inactivation may remove this protection.…”

Zinc finger protein 185 is a liver metastasis-associated factor in colon cancer patients

“…The expression and localization of ZNF185 in prostate cancer cells and fibroblasts revealed that, in addition to F-actin stress fibers, ZNF185 localized to several other cytoskeleton-related areas, including focal adhesions and filopodia/ lamellipodia. ZNF185 was also shown to contain an ATD in the N-terminal region and binds to F-actin directly through the ATD, but not the LIM domains (17). Thus, ZNF185 interacts with F-actin and focal adhesion components.…”

“…ZNF185 is located on chromosome Xq28 and is expressed in the kidney, prostate, pancreas, blood, placenta and ovary, but not in the liver (15). The complete ZNF185 gene was originally cloned from normal human prostate tissue by Zhang et al (17). The expression and localization of ZNF185 in prostate cancer cells and fibroblasts revealed that, in addition to F-actin stress fibers, ZNF185 localized to several other cytoskeleton-related areas, including focal adhesions and filopodia/ lamellipodia.…”

“…LIM and SH3 protein 1 was also identified as a promoter of breast cancer, ovarian cancer and hepatocellular carcinoma and is suggested to be the transcriptional target of p53 (25)(26)(27). ZNF185 gene expression was only shown to be downregulated in matched normal tissues from prostate cancer, craniocervical squamous cell carcinoma and non-small-cell lung cancer (16,17,28,29). Vanaja et al (16) reported that the gene expression levels in high-grade (Gleason score 9) prostate cancer cells were suppressed more compared to intermediate grade (Gleason score 6) prostate cancer cells (16).…”

“…ZNF185 is located on chromosome Xq28 and is expressed in the kidney, prostate, pancreas, blood, placenta and ovary, but not in the liver (15). ZNF185 may be involved in regulating cellular differentiation and/or proliferation (16,17). Certain LIM domain-containing proteins were previously shown to be involved in carcinogenic processes (18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”