ASPP2 suppresses squamous cell carcinoma via RelA/p65-mediated repression of p63

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Squamous cell carcinoma (SCC) is a highly malignant cancer often resistant to treatment.
• Existing mouse models typically involve multiple gene mutations, limiting spontaneous SCC research.
• Few models exist for spontaneous SCC arising from single gene deletions.

Purpose of the Study:

• To develop a novel, haploinsufficient mouse model for spontaneous squamous cell carcinoma (SCC).
• To investigate the role of the Tp53BP2 gene, encoding ASPP2, in SCC development.
• To elucidate the mechanism by which ASPP2 suppresses SCC, focusing on its interaction with p63 and NF-κB signaling.

Main Methods:

• Generation of a haploinsufficient mouse model by deleting exon 3 of the Tp53BP2 gene in one allele.
• Analysis of keratinocyte differentiation and expression of ASPP2 and p63 in vitro and in vivo.
• Investigation of the requirement for p63 and p53 in SCC development in the ASPP2 model.
• Mechanistic studies involving IκB binding, NF-κB transcription complex activation, and p63 repression.

Main Results:

• The ASPP2(Δexon3/+) mouse model spontaneously develops SCC.
• ASSP2 expression is inversely correlated with p63 expression during keratinocyte differentiation.
• Up-regulation of p63 is essential for SCC development in this model; p63 heterozygosity prevents SCC.
• ASSP2 suppresses ΔNp63 expression by enhancing NF-κB signaling, leading to p63 repression.

Conclusions:

• ASSP2 acts as a tumor suppressor in SCC by inhibiting p63 expression through the NF-κB pathway.
• Reduced ASPP2 expression correlates with tumor metastasis and elevated p63 in human head and neck SCCs.
• This study identifies a novel mechanism of SCC suppression involving ASPP2, p63, and inflammatory signaling.