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

Oncogene volume 22, pages 5519–5524 (2003)Cite this article

Abstract

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.

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Abbreviations

BCC:

basal cell carcinoma

bp:

base pair

Cdk:

Cyclin-dependent kinase

HDF:

human diploid fibroblasts

MSP:

methylation-specific PCR

SCC:

squamous cell carcinoma

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Acknowledgements

We thank Jens-Oliver Funk and the members of the Molecular Oncology lab for comments and discussions, and Bert Vogelstein and Axel Ullrich for providing cell lines. Heiko Hermeking's laboratory is supported by the Max-Planck-Society, the Rudolf-Bartling foundation and the Dr Mildred-Scheel foundation (Grant 10-1945).

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Author notes

  1. Dimitri Lodygin and Amir S Yazdi: These two authors contributed equally to this work

Authors and Affiliations

  1. Molecular Oncology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18A, Martinsried near Munich, D-82152, Germany

    Dimitri Lodygin & Heiko Hermeking

  2. Department of Dermatology, Ludwig-Maximilians-University of Munich, Germany

    Amir S Yazdi, Christian A Sander & Thomas Herzinger

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  1. Dimitri Lodygin
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Correspondence to Heiko Hermeking.

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Lodygin, D., Yazdi, A., Sander, C. et al. Analysis of 14-3-3σ expression in hyperproliferative skin diseases reveals selective loss associated with CpG-methylation in basal cell carcinoma. Oncogene 22, 5519–5524 (2003). https://doi.org/10.1038/sj.onc.1206854

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