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

Abstract

TP53 is the most frequently mutated gene in human cancer. Many mutant p53 proteins exert oncogenic gain-of-function (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.

• Authors: Rasoul Pourebrahim, Yun Zhang, Bin Liu, Ruli Gao, Shunbin Xiong, Patrick P Lin, Mark J McArthur, Michael C Ostrowski, Guillermina Lozano
• Journal: Genes & development (Genes Dev) Vol. 31 Issue 18 Pg. 1847-1857 (09 15 2017) ISSN: 1549-5477 [Electronic] United States
• PMID: 29021240 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2017 Pourebrahim et al.; Published by Cold Spring Harbor Laboratory Press.

Chemical References

• Ets2 protein, mouse
• Proto-Oncogene Protein c-ets-2
• RNA, Small Nucleolar
• Tumor Suppressor Protein p53

Topics

• Animals
• Bone Neoplasms (genetics, pathology)
• Down-Regulation
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Liver Neoplasms (genetics, secondary)
• Lung Neoplasms (genetics, secondary)
• Mice
• Mice, Knockout
• Mutation
• Neoplasm Metastasis
• Oligonucleotide Array Sequence Analysis
• Osteoblasts (metabolism, pathology)
• Osteosarcoma (genetics, secondary)
• Proto-Oncogene Protein c-ets-2 (genetics)
• RNA, Small Nucleolar (genetics)
• Tumor Suppressor Protein p53 (genetics)
• Up-Regulation