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

Abstract

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 mutation (p53R172H) or loss in osteoblasts. Our study confirmed that mutant mice developed osteosarcomas with increased metastasis as compared with-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 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.

Aberrant expression of ETS1 and ETS2 proteins in cancer

“…Whereas ETS1 knockdown had no effect on mtp53 target gene expression, ETS2 depletion reproduced changes in gene expression that occur on mtp53 depletion suggesting close relationship between mtp53 and ETS2. The observation that ETS2 interacts with various mtp53 (R175H, R248Q, R248W, R249S, R273H, R273L, and R280K) suggests that through ETS2 binding, different mtp53 proteins reveal oncogenic potential through common mechanisms consistent with the recent MD Anderson study (172). …”

“…Very recently, the Lozano’s group elucidated how GOF mtp53 drove cancer metastasis by developing a traceable osteosarcoma mouse model (172). They showed that mtp 53 mice developed osteosarcomas with increased metastasis as compared with p53 -null mice.…”

“…They showed that mtp 53 mice developed osteosarcomas with increased metastasis as compared with p53 -null mice. The RNA-seq analysis of tumors identified a cluster of small nucleolar RNAs (snoRNAs) that were highly up-regulated in mtp53 mutant tumors with enrichment of Ets2 transcription factor-binding site (172). Consistently, homozygous deletion of Ets2 in p53 mutant mice resulted in significant down-regulation of snoRNAs with simultaneous reversion of the pro-metastatic phenotype of tumors induced my mtp53, which had no effect on the growth of primary osteosarcoma.…”

“…Consistently, homozygous deletion of Ets2 in p53 mutant mice resulted in significant down-regulation of snoRNAs with simultaneous reversion of the pro-metastatic phenotype of tumors induced my mtp53, which had no effect on the growth of primary osteosarcoma. Thus Ets2 inhibition is a potential therapeutic vulnerability in mtp53 mutant osteosarcomas (172). …”

“…Conversely, Ets2 has a tumor-suppressive role by upregulation the transcription of p16 INK4a although it stimulates the transcription of Cyclin D1 . The situation is completely reversed when the cells have mutant p53; ETS2 reveals oncogenic function by stabilizing mutant p53 as evidenced by the recent study employing gene engineered mice (172). The authors concluded that blocking Ets2 activity is essential to prevent lung metastasis of osteosarcoma.…”