Analysis of 14-3-3sigma expression in hyperproliferative skin diseases reveals selective loss associated with CpG-methylation in basal cell carcinoma.
The p53-regulated 14-3-3sigma gene encodes an inhibitor of cell cycle progression essential for senescence and clonal evolution of keratinocytes in vitro. Here we analysed the in vivo expression of 14-3-3sigma protein in several skin diseases, which are characterized by hyperproliferative keratinocytes. Unexpectedly, the 14-3-3sigma protein was expressed at high levels in psoriasis (11 of 11 patients), condylomata acuminata (11/11), actinic keratoses (11/11) and squamous cell carcinomas (SCC) (11/11). However, keratinocytes that had undergone transformation to basal cell carcinoma (BCC) showed partial (10 of 41; 24.4%) or complete (19 of 41; 46.3%) loss of 14-3-3sigma protein expression. BCC (5/5), SCC (6/6) and actinic keratoses (7/7) concomitantly expressed the p53-homolog p63 and 14-3-3sigma at high levels, ruling out potential inhibitory effects of p63 isoforms on 14-3-3sigma transcription as the basis for loss of 14-3-3sigma expression. Of 41 BCC samples isolated by laser-capture microdissection, 28 (68.3%) showed CpG-hypermethylation of the 14-3-3sigma promoter combined with reduced or absent 14-3-3sigma protein levels in 22 cases (78.6%). Since it has been reported that BCC retain wild-type p16(INK4A) and here BCC with CpG-methylation of 14-3-3sigma did not show CpG-methylation of p16(INK4A) (0/17), silencing of 14-3-3sigma may contribute to evasion of senescence in BCC. As experimental removal of 14-3-3sigma sensitizes to DNA damage, silencing of 14-3-3sigma may explain the high efficacy of radiation therapy in the treatment of BCC.
Lodygin
Dimitri
D
Molecular Oncology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18A, D-82152 Martinsried near Munich, Germany.
Yazdi
Amir S
AS
Sander
Christian A
CA
Herzinger
Thomas
T
Hermeking
Heiko
H
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D002280:Basal Cell Carcinoma / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D005092:Exonucleases / Q000096:biosynthesis / Q000235:genetics*; D005095:Exoribonucleases; D006801:Humans; D009363:Neoplasm Proteins; D012871:Skin Diseases / Q000473:pathology
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human