| First Author | Gnana-Prakasam JP | Year | 2013 |
| Journal | Invest Ophthalmol Vis Sci | Volume | 54 |
| Issue | 1 | Pages | 63-71 |
| PubMed ID | 23169885 | Mgi Jnum | J:214358 |
| Mgi Id | MGI:5588800 | Doi | 10.1167/iovs.12-10312 |
| Citation | Gnana-Prakasam JP, et al. (2013) Loss of Hfe leads to progression of tumor phenotype in primary retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 54(1):63-71 |
| abstractText | PURPOSE: Hemochromatosis is a disorder of iron overload arising mostly from mutations in HFE. HFE is expressed in retinal pigment epithelium (RPE), and Hfe(-/-) mice develop age-related iron accumulation and retinal degeneration associated with RPE hyperproliferation. Here, the mechanism underlying the hyperproliferative phenotype in RPE was investigated. METHODS: Cellular senescence was monitored by beta-galactosidase activity. Gene expression was monitored by real-time PCR. Survivin was analyzed by Western blot and immunofluorescence. Migration and invasion were monitored using appropriate kits. Glucose transporters (GLUTs) were monitored by 3-O-methyl-D-glucose uptake. Histone deacetylases (HDACs) were studied by monitoring catalytic activity and acetylation status of histones H3/H4. RESULTS: Hfe(-/-) RPE cells exhibited slower senescence rate and higher survivin expression than wild type cells. Hfe(-/-) cells migrated faster and showed greater glucose uptake and increased expression of GLUTs. The expression of HDACs and DNA methyltransferase (DNMTs) also was increased. Similarly, RPE cells from hemojuvelin (Hjv)-knockout mice, another model of hemochromatosis, also had increased expression of GLUTs, HDACs, and DNMTs. The expression of Slc5a8 was decreased in Hfe(-/-) RPE cells, but treatment with a DNA methylation inhibitor restored the transporter expression, indicating involvement of DNA methylation in the silencing of Slc5a8 in Hfe(-/-) cells. CONCLUSIONS: RPE cells from iron-overloaded mice exhibit several features of tumor cells: decreased senescence, enhanced migration, increased glucose uptake, and elevated levels of HDACs and DNMTs. These features are seen in Hfe(-/-) RPE cells as well as in Hjv(-/-) RPE cells, providing a molecular basis for the hyperproliferative phenotype of Hfe(-/-) and Hjv(-/-) RPE cells. |
