Analysis of 14-3-3σ expression in hyperproliferative skin diseases reveals selective loss associated with CpG-methylation in basal cell carcinoma

• Published in: Oncogene Vol. 22; no. 35; pp. 5519 - 5524
• Main Authors: LODYGIN, Dimitri, YAZDI, Amir S, SANDER, Christian A, HERZINGER, Thomas, HERMEKING, Heiko
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 21.08.2003; Nature Publishing Group
• Subjects: Basal cell carcinoma; Biological and medical sciences; Cell cycle; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Condyloma acuminatum; CpG islands; DNA damage; DNA methylation; Fundamental and applied biological sciences. Psychology; INK4a protein; Isoforms; Keratinocytes; Lasers; Molecular and cellular biology; p16 Protein; p53 Protein; Proteins; Psoriasis; Radiation therapy; Senescence; Skin cancer; Skin diseases; Squamous cell carcinoma; Transcription; Skin disease; Basal cell carcinoma; CpG-methylation; tumour suppressor; Analysis; Cell cycle; Loss; Keratinocyte; Malignant tumor; keratinocytes; Methylation
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206854

The p53-regulated 14-3-3σ 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 14-3-3σ protein in several skin diseases, which are characterized by hyperproliferative keratinocytes. Unexpectedly, the 14-3-3σ 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 14-3-3σ protein expression. BCC (5/5), SCC (6/6) and actinic keratoses (7/7) concomitantly expressed the p53-homolog p63 and 14-3-3σ at high levels, ruling out potential inhibitory effects of p63 isoforms on 14-3-3σ transcription as the basis for loss of 14-3-3σ expression. Of 41 BCC samples isolated by laser-capture microdissection, 28 (68.3%) showed CpG-hypermethylation of the 14-3-3σ promoter combined with reduced or absent 14-3-3σ protein levels in 22 cases (78.6%). Since it has been reported that BCC retain wild-type p16INK4A and here BCC with CpG-methylation of 14-3-3σ did not show CpG-methylation of p16INK4A (0/17), silencing of 14-3-3σ may contribute to evasion of senescence in BCC. As experimental removal of 14-3-3σ sensitizes to DNA damage, silencing of 14-3-3σ may explain the high efficacy of radiation therapy in the treatment of BCC.