title: Physical association of HDAC1 and HDAC2 with p63 mediates transcriptional repression and tumor maintenance in squamous cell carcinoma.
abstract: Squamous cell carcinoma (SCC) is a treatment-refractory subtype of human cancer arising from stratified epithelium of the skin, lung, esophagus, oropharynx, and other tissues. A unifying feature of SCC is high-level expression of the p53-related protein p63 (TP63) in 80% of cases. The major protein isoform of p63 expressed in SCC is ΔNp63α, an N-terminally truncated form which functions as a key SCC cell survival factor by mechanisms that are unclear. In this study, we show that ΔNp63α associates with histone deacetylase 1 (HDAC1) and HDAC2 to form an active transcriptional repressor complex that can be targeted to therapeutic advantage. Repression of proapoptotic Bcl-2 family member genes including p53 upregulated modulator of apoptosis (PUMA) by p63/HDAC is required for survival of SCC cells. Cisplatin chemotherapy, a mainstay of SCC treatment, promotes dissociation of p63 and HDAC from the PUMA promoter, leading to increased histone acetylation, PUMA activation, and apoptosis. These effects are recapitulated upon targeting the p63/HDAC complex selectively with class I/II HDAC inhibitors using both in vitro and in vivo models. Sensitivity to HDAC inhibition is directly correlated with p63 expression and is abrogated in tumor cells that overexpress endogenous Bcl-2. Together, our results elucidate a mechanism of p63-mediated transcriptional repression and they identify the ΔNp63α/HDAC complex as an essential tumor maintenance factor in SCC. In addition, our findings offer a rationale to apply HDAC inhibitors for SCC treatment.
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Ramsey
authors.forename: Lei
authors.initials: L
authors.lastname: He
authors.forename: Nicole
authors.initials: N
authors.lastname: Forster
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ory
authors.forename: Leif W
authors.initials: LW
authors.lastname: Ellisen
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D002945:Cisplatin