A role for Bach1 and HO-2 in suppression of basal and UVA-induced HO-1 expression in human keratinocytes

• Published in: Free radical biology & medicine 2010-01, Vol.48 (2), p.196-206
• Main Authors: Zhong, Julia Li, Raval, Chintan, Edwards, Gavin P., Tyrrell, Rex M.
• Format: Article
• Language: English
• Subjects: Bach1; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - metabolism; Fanconi Anemia Complementation Group Proteins - genetics; Fanconi Anemia Complementation Group Proteins - metabolism; Fibroblasts - metabolism; Fibroblasts - pathology; Fibroblasts - radiation effects; Free radicals; Gene Expression Regulation, Enzymologic - genetics; HeLa Cells; Heme Oxygenase (Decyclizing) - genetics; Heme Oxygenase (Decyclizing) - metabolism; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; HO-1; HO-2; Humans; Keratinocytes - metabolism; Keratinocytes - pathology; Keratinocytes - radiation effects; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2; Oxidative Stress - genetics; Radiation Tolerance - genetics; RNA, Small Interfering - genetics; Skin - pathology; Transfection; Ultraviolet Rays; UVA
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2009.10.037

Ultraviolet A (UVA) radiation is an oxidizing agent that strongly induces the heme oxygenase 1 (HO-1) gene and expression of the protein in cultured human skin fibroblasts but weakly induces it in skin keratinocytes. Lower basal levels of HO-1 and much higher basal levels of HO-2 protein are observed in keratinocytes compared with fibroblasts. Using both overexpression and knockdown approaches, we demonstrate that HO-2 modulates basal and UVA-induced HO-1 protein levels, whereas HO-1 levels do not affect HO-2 levels in skin fibroblasts and keratinocytes. Silencing of Bach1 strongly increases HO-1 levels in transformed HaCaT keratinocytes and these HO-1 levels are not further increased by either UVA irradiation or silencing of HO-2. This is consistent with the conclusion that high constitutive levels of HO-2 expression in keratinocytes are responsible for the resistance of these cells to HO-1 induction by UVA radiation and that Bach1 plays a predominant role in influencing the lack of HO-1 expression in keratinocytes. Bach1 inhibition leading to HO-1 induction reduced UVA-irradiation-induced damage as monitored both by the extent of LDH release and by nuclear condensation, so that Bach1 inhibition seems to protect against UVA-irradiation-induced damage in keratinocytes.