ΔNp63 isoforms regulate CD44 and keratins 4, 6, 14 and 19 in squamous cell carcinoma of head and neck
- 12 October 2007
- journal article
- research article
- Published by Wiley in The Journal of Pathology
- Vol. 213 (4), 384-391
- https://doi.org/10.1002/path.2237
Abstract
The human p63 gene codes for multiple protein isoforms and is commonly over‐expressed in squamous cell carcinoma of head and neck (SCCHN). This expression is predominantly of the ΔN‐ and β‐isoforms, the former lacking the p53‐related transactivation domain. p63 can activate or repress transcription of p53 and p73 target genes, but also has unique transcriptional targets and, unlike other p53 family members, is required for normal development and differentiation of squamous epithelia. We have identified novel targets of p63, using microarray analysis of SCCHN cells that stably over‐express individual ΔNp63 isoforms. All three isoforms induced expression of the cancer stem cell marker, CD44, with the ΔNp63β isoform showing strongest induction. Using chromatin immunoprecipitation, we were unable to show direct binding of p63 to the CD44 promoter, but found that p63 specifically increased expression of CD44 lacking variant exon 2. Each of the ΔNp63 isoforms up‐regulated expression of keratins 6A and 14 and down‐regulated expression of keratins 4 and 19, in keeping with their expression patterns in SCCHN. The data strengthen the idea that p63 has key roles in regulating normal and abnormal differentiation processes through both induction and repression of genes with opposite functions. The identification of up‐regulation and differential splicing of CD44 following p63 over‐expression indicates roles in the regulation of adhesion, metastasis and the cancer stem cell phenotype. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.This publication has 42 references indexed in Scilit:
- A Functional Enhancer of Keratin14 Is a Direct Transcriptional Target of ΔNp63Journal of Investigative Dermatology, 2007
- p63 induces key target genes required for epidermal morphogenesisProceedings of the National Academy of Sciences, 2007
- Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinomaProceedings of the National Academy of Sciences of the United States of America, 2007
- p63 regulates proliferation and differentiation of developmentally mature keratinocytesGenes & Development, 2006
- Glioma stem cells promote radioresistance by preferential activation of the DNA damage responseNature, 2006
- New p63 targets in keratinocytes identified by a genome-wide approachThe EMBO Journal, 2006
- The tumour-suppressor protein ASPP1 is nuclear in human germ cells and can modulate ratios of CD44 exon V5 spliced isoforms in vivoOncogene, 2006
- AEC-Associated p63 Mutations Lead to Alternative Splicing/Protein Stabilization of p63 and Modulation of Notch SignalingCell Cycle, 2005
- Characterization of cd44v6 isoforms in head-and-neck squamous-cell carcinomaInternational Journal of Cancer, 1999
- Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts hyaluronate metabolism in the skin and impairs keratinocyte proliferation.Genes & Development, 1997