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E2F suppression and Sp1 overexpression are sufficient to induce the differentiation-specific marker, transglutaminase type 1, in a squamous cell carcinoma cell line

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Abstract

Recently, E2F function has expanded to include the regulation of differentiation in human epidermal keratinocytes (HEKs). We extend these findings to report that in HEKs, Sp1 is a differentiation-specific activator and a downstream target of E2F-mediated suppression of the differentiation-specific marker, transglutaminase type 1 (TG-1). Deletion of elements between −0.084 to −0.034 kb of the TG-1 promoter disabled E2F1-induced suppression of promoter activity. Electrophoretic mobility shift assays (EMSAs) demonstrated that Sp1 and Sp3 bound this region. Protein expression analysis suggested that squamous differentiation was accompanied by increased Sp1/Sp3 ratio. Cotransfection of proliferating HEKs or the squamous cell carcinoma (SCC) cell line, KJD-1/SV40, with an E2F inhibitor (E2Fd/n) and Sp1 expression plasmid was sufficient to activate the TG-1 promoter. The suppression of Sp1 activity by E2F in differentiated cells appeared to be indirect since we found no evidence of an Sp1/E2F coassociation on the TG-1 promoter fragment. Moreover, E2F inhibition in the presence of a differentiation stimulus induced Sp1 protein. These data demonstrate that (i) Sp1 can act as a differentiation stimulus, (ii) E2F-mediated suppression of differentiation-specific markers is indirect via Sp1 inhibition and (iii) a combination of E2F inhibition and Sp1 activation could form the basis of a differentiation therapy for SCCs.

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Acknowledgements

We are grateful to Dr Ibtissam Abdul-Jabbar for her help with FACS. This work was supported by grants awarded from The Garnett Passe and Rodney Williams Memorial Foundation, The Australian National Health and Medical Research Council (#301075) and the Association for International Cancer Research. NAS is sponsored by a Principal Research Fellowship awarded by the Garnett Passe and Rodney Williams Memorial Foundation. CP is supported by a University of Queensland Postdoctoral Fellowship. CFW is sponsored by an Australian Postgraduate Award.

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Authors and Affiliations

  1. Epithelial Pathobiology Group, Cancer Biology Programme, Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Queensland, 4102, Australia

    Chung Fai Wong, Liam M Barnes, Alison L Dahler, Louise Smith, Claudia Popa, Magdalena M Serewko-Auret & Nicholas A Saunders

  2. Department of Physiology and Pharmacology, University of Queensland, St Lucia, Queensland, 4067, Australia

    Nicholas A Saunders

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  1. Chung Fai Wong
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  2. Liam M Barnes
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  3. Alison L Dahler
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  4. Louise Smith
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  5. Claudia Popa
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Correspondence to Nicholas A Saunders.

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Wong, C., Barnes, L., Dahler, A. et al. E2F suppression and Sp1 overexpression are sufficient to induce the differentiation-specific marker, transglutaminase type 1, in a squamous cell carcinoma cell line. Oncogene 24, 3525–3534 (2005). https://doi.org/10.1038/sj.onc.1208372

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