PDF(Pubmed)
Abstract：
Aberrant expression of the E26 transformation-specific (ETS) transcription factors characterizes numerous human malignancies. Many of these proteins, including EWS:FLI1 and EWS:ERG fusions in Ewing sarcoma (EwS) and TMPRSS2:ERG in prostate cancer (PCa), drive oncogenic programs via binding to GGAA repeats. We report here that both EWS:FLI1 and ERG bind and transcriptionally activate GGAA-rich pericentromeric heterochromatin. The respective pathogen-like HSAT2 and HSAT3 RNAs, together with LINE, SINE, ERV, and other repeat transcripts, are expressed in EwS and PCa tumors, secreted in extracellular vesicles (EVs), and are highly elevated in plasma of patients with EwS with metastatic disease. High human satellite 2 and 3 (HSAT2,3) levels in EWS:FLI1- or ERG-expressing cells and tumors were associated with induction of G2/M checkpoint, mitotic spindle, and DNA damage programs. These programs were also activated in EwS EV-treated fibroblasts, coincident with accumulation of HSAT2,3 RNAs, proinflammatory responses, mitotic defects, and senescence. Mechanistically, HSAT2,3-enriched cancer EVs induced cGAS-TBK1 innate immune signaling and formation of cytosolic granules positive for double-strand RNAs, RNA-DNA, and cGAS. Hence, aberrantly expressed ETS proteins derepress pericentromeric heterochromatin, yielding pathogenic RNAs that transmit genotoxic stress and inflammation to local and distant sites. Monitoring HSAT2,3 plasma levels and preventing their dissemination may thus improve therapeutic strategies and blood-based diagnostics.
摘要：
E26转化特异性（ETS）转录因子的异常表达表征了许多人类恶性肿瘤。这些蛋白质中的许多，包括EWS：FLI1和EWS：尤因肉瘤（EwS）的ERG融合和TMPRSS2：前列腺癌（PCa）的ERG，通过结合GGAA重复来驱动致癌程序。我们在此报告EWS：FLI1和ERG都结合并转录激活富含GGAA的着丝粒异染色质。各自的病原体样HSAT2和HSAT3RNA，和LINE一起,SINE,ERV,和其他重复抄本，在EwS和PCa肿瘤中表达，在细胞外囊泡（EV）中分泌，并且在患有转移性疾病的EwS患者的血浆中高度升高。EWS中的高人类卫星2和3（HSAT2,3）水平：表达FLI1或ERG的细胞和肿瘤与G2/M检查点的诱导有关，有丝分裂纺锤体，和DNA损伤计划。这些程序也在EwSEV处理的成纤维细胞中被激活，与HSAT2,3RNA的积累相吻合，促炎反应，有丝分裂缺陷,和衰老。机械上,富含HSAT2,3的癌症EVs诱导cGAS-TBK1先天性免疫信号和双链RNA阳性的胞浆颗粒的形成，RNA-DNA,和CGAS。因此，异常表达的ETS蛋白抑制着丝粒周围异染色质，产生将基因毒性应激和炎症传递到局部和远处部位的致病性RNA。因此，监测HSAT2,3血浆水平并防止其传播可以改善治疗策略和基于血液的诊断。
