Integrative genome analysis of somatic p53 mutant osteosarcomas identifies Ets2-dependent regulation of small nucleolar RNAs by mutant p53 protein

Rasoul Pourebrahim, Yun Zhang, Bin Liu, Ruli Gao, Shunbin Xiong, Patrick P. Lin, Mark J. McArthur, Michael C. Ostrowski, Guillermina Lozano*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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 languageEnglish (US)
Pages (from-to)1847-1857
Number of pages11
JournalGenes and Development
Volume31
Issue number18
DOIs
StatePublished - Sep 15 2017
Externally publishedYes

Keywords

  • Ets2
  • Metastasis
  • Osteosarcoma
  • P53
  • SnoRNA

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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