HOTAIRprimes the Ewing sarcoma family of tumors for tumorigenesis via epigenetic dysregulation involving LSD1

Abstract

AbstractThe EWS-FLI1 fusion protein drives oncogenesis in the Ewing sarcoma family of tumors (ESFT) in humans, but its toxicity in normal cells requires additional cellular events for oncogenesis. We show that the lncRNAHOTAIRmaintains cell viability in the presence of EWS-FLI1 and redirects epigenetic regulation in ESFT.HOTAIRis consistently overexpressed in ESFTs and is not driven by EWS-FLI1. Repression ofHOTAIRin ESFT cell lines significantly reduces anchorage-independent colony formation in vitro and impairs tumor xenograft growth in vivo. Overexpression ofHOTAIRin human mesenchymal stem cells (hMSCs), a putative cell of origin of ESFT, and IMR90 cells induces colony formation. Critically, HOTAIR-expressing hMSCs and IMR90 cells remain viable with subsequentEWS-FLI1expression.HOTAIRinduces histone modifications and gene repression through interaction with the epigenetic modifier LSD1 in ESFT cell lines and hTERT-hMSCs. Our findings suggest thatHOTAIRmaintains ESFT viability through epigenetic dysregulation.SignificanceWhile theEWS-FLI1fusion gene was determined to be the oncogenic driver in the overwhelming majority of ESFT, it is toxic to cell physiology and requires one or more additional molecular events to maintain cell viability. As these tumors have surprisingly few genetic mutations at diagnosis, epigenetic changes have been considered to be such an event, but the mechanism by which these changes are driven remains unclear. Our work shows thatHOTAIRis consistently expressed among ESFT and induces epigenetic and gene expression changes that cooperate in tumorigenesis. Furthermore, expression ofHOTAIRallows for cell viability in the setting of subsequentEWS-FLI1expression. Our findings elucidate new steps of malignant transformation in this cancer and identify novel therapeutic targets.