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

Siddiqui, H.; Selich-Anderson, J.; Felgenhauer, J.; Fitch, J.; Nadella, V.; Taslim, C.; Tomino, L.; Theisen, E.; Otsuru, S.; Horwitz, E.; Lessnick, S. L.; White, P.; Shah, N.

doi:10.1101/244558

bioRxiv · 10.1101/244558

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

Siddiqui, H.·Selich-Anderson, J.·Felgenhauer, J.·Fitch, J.·Nadella, V.·Taslim, C.·Tomino, L.·Theisen, E.·Otsuru, S.·Horwitz, E.·Lessnick, S. L.·White, P.·Shah, N.

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Abstract

The 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 lncRNA HOTAIR maintains cell viability in the presence of EWS-FLI1 and redirects epigenetic regulation in ESFT. HOTAIR is consistently overexpressed in ESFTs and is not driven by EWS-FLI1. Repression of HOTAIR in ESFT cell lines significantly reduces anchorage-independent colony formation in vitro and impairs tumor xenograft growth in vivo. Overexpression of HOTAIR in 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 subsequent EWS-FLI1 expression. HOTAIR induces histone modifications and gene repression through interaction with the epigenetic modifier LSD1 in ESFT cell lines and hTERT-hMSCs. Our findings suggest that HOTAIR maintains ESFT viability through epigenetic dysregulation.\n\nSignificanceWhile the EWS-FLI1 fusion 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 that HOTAIR is consistently expressed among ESFT and induces epigenetic and gene expression changes that cooperate in tumorigenesis. Furthermore, expression of HOTAIR allows for cell viability in the setting of subsequent EWS-FLI1 expression. Our findings elucidate new steps of malignant transformation in this cancer and identify novel therapeutic targets.

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Siddiqui, H., Selich-Anderson, J., Felgenhauer, J., Fitch, J., Nadella, V., Taslim, C., Tomino, L., Theisen, E., Otsuru, S., Horwitz, E., Lessnick, S. L., White, P., Shah, N.. 2018-01-08. HOTAIR primes the Ewing sarcoma family of tumors for tumorigenesis via epigenetic dysregulation involving LSD1. https://doi.org/10.1101/244558

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