Abstract
TP53 is the most frequently mutated gene in human cancer. Many mutant p53 proteins exert oncogenic gain-offunction (GOF) properties that contribute to metastasis, but the mechanisms mediating these functions remain poorly defined in vivo. To elucidate how mutant p53 GOF drives metastasis, we developed a traceable somatic osteosarcoma mouse model that is initiated with either a single p53 mutation (p53R172H) or p53 loss in osteoblasts. Our study confirmed that p53 mutant mice developed osteosarcomas with increased metastasis as compared with p53-null mice. Comprehensive transcriptome RNA sequencing (RNA-seq) analysis of 16 tumors identified a cluster of small nucleolar RNAs (snoRNAs) that are highly up-regulated in p53 mutant tumors. Regulatory element analysis of these deregulated snoRNA genes identified strong enrichment of a common Ets2 transcription factor-binding site. Homozygous deletion of Ets2 in p53 mutant mice resulted in strong down-regulation of snoRNAs and reversed the prometastatic phenotype of mutant p53 but had no effect on osteosarcoma development, which remained 100% penetrant. In summary, our studies identify Ets2 inhibition as a potential therapeutic vulnerability in p53 mutant osteosarcomas.
Original language | English (US) |
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Pages (from-to) | 1847-1857 |
Number of pages | 11 |
Journal | Genes and Development |
Volume | 31 |
Issue number | 18 |
DOIs | |
State | Published - Sep 15 2017 |
Keywords
- Ets2
- Metastasis
- Osteosarcoma
- P53
- SnoRNA
ASJC Scopus subject areas
- Genetics
- Developmental Biology
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