Anthracyclines disaggregate and restore mutant p63 function: a potential therapeutic approach for AEC syndrome

Cell Death Discovery, vol. 11, pp. 24

Abstract

Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) syndrome is a rare genetic disorder caused by mutations in the TP63 gene, which encodes a transcription factor essential for epidermal gene expression. A key feature of AEC syndrome is chronic skin erosion, for which no effective treatment currently exists. Our previous studies demonstrated that mutations associated with AEC syndrome lead to p63 protein misfolding and aggregation, exerting a dominant-negative effect. By performing a high-throughput screening of epigenetic and FDA-approved compounds in a co-transfection model of wild-type and mutant p63, we found that two compounds, Doxorubicin and Epirubicin, alleviate protein aggregation and restore p63 transactivation function. Moreover, treatment with these compounds reduced protein aggregation and restored the expression of keratinocyte-specific p63 target genes in primary keratinocytes derived from a conditional ΔNp63αL514F knock-in AEC mouse model, which mimics the ectodermal defects and skin erosions characteristic of AEC syndrome. A chemical analog of Doxorubicin, diMe-Doxorubicin, which exhibits lower tissue and organ toxicity, was also found to be effective in promoting the disaggregation of mutant p63 and rescuing its transcriptional activity. Our findings identify compounds that can partially resolve mutant p63 aggregation, increase its monomeric isoform, and reactivate its transcriptional function. These results suggest potential therapeutic efficacy for treating skin erosions in AEC syndrome.

Authors 8

1. Fabiana Boncimino

   Harvard University · Massachusetts General Hospital

   Affiliation as printed

   Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA

2. Ludovica D’Auria

   CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) · University of Naples Federico II

   Affiliation as printed

   CEINGE Biotecnologie Avanzate Franco Salvatore, 80145, Naples, Italy

   Department of Biology, University of Naples Federico II, 80126, Naples, Italy

3. Kristina A. Todorova

   Harvard University · Massachusetts General Hospital

   Affiliation as printed

   Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA

4. Sabina Y. van der Zanden Aachen Department of Cell and Chemical Biology Oncode Institute

   Leiden University Medical Center

   Affiliation as printed

   Department of Cell and Chemical Biology, ONCODE Institute, Leiden University Medical Center, 2333 ZC, Leiden, The Netherlands

5. Jacques Neefjes Aachen Department of Cell and Chemical Biology Oncode Institute

   Leiden University Medical Center

   Affiliation as printed

   Department of Cell and Chemical Biology, ONCODE Institute, Leiden University Medical Center, 2333 ZC, Leiden, The Netherlands

6. Anna Mandinova corresponding

   Broad Institute · Harvard University · Massachusetts General Hospital · Harvard Stem Cell Institute

   Affiliation as printed

   Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA, 02142, USA. amandinova@mgh.harvard.edu

   Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA. amandinova@mgh.harvard.edu

   Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge, MA, 02138, USA. amandinova@mgh.harvard.edu

   Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA

7. Caterina Missero corresponding

   CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) · University of Naples Federico II

   Affiliation as printed

   CEINGE Biotecnologie Avanzate Franco Salvatore, 80145, Naples, Italy. missero@ceinge.unina.it

   Department of Biology, University of Naples Federico II, 80126, Naples, Italy. missero@ceinge.unina.it

   Department of Biology, University of Naples Federico II, 80126, Naples, Italy

8. Stefano Sol corresponding

   Harvard University · Massachusetts General Hospital · CEINGE Biotecnologie Avanzate Franco Salvatore (Italy)

   Affiliation as printed

   CEINGE Biotecnologie Avanzate Franco Salvatore, 80145, Naples, Italy. ssol@mgh.harvard.edu

   Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA. ssol@mgh.harvard.edu

   CEINGE Biotecnologie Avanzate Franco Salvatore, 80145, Naples, Italy

   Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA