Abstract

Endometrial stromal sarcoma (ESS) is the second most common subtype of uterine mesenchymal cancer, after leiomyosarcoma, and oncogenic fusion proteins are found in many ESS. Our previous studies demonstrated transforming properties and diagnostic relevance of the fusion oncoprotein YWHAE–NUTM2 in high-grade endometrial stromal sarcoma (HG-ESS) and showed that cyclin D1 is a diagnostic biomarker in these HG-ESS. However, YWHAE–NUTM2 mechanisms of oncogenesis and roles in cyclin D1 expression have not been characterized. In the current studies, we show YWHAE-NUTM2 complexes with both BRAF/RAF1 and YAP/TAZ in HG-ESS. These interactions are functionally relevant because YWHAE-NUTM2 knockdown in HG-ESS and other models inhibits RAF/MEK/MAPK phosphorylation, cyclin D1 expression, and cell proliferation. Further, cyclin D1 knockdown in HG-ESS dephosphorylates RB1 and inhibits proliferation. In keeping with these findings, we show that MEK and CDK4/6 inhibitors have anti-proliferative effects in HG-ESS, and combinations of these inhibitors have synergistic activity. These findings establish that YWHAE-NUTM2 regulates cyclin D1 expression and cell proliferation by dysregulating RAF/MEK/MAPK and Hippo/YAP-TAZ signaling pathways. Recent studies demonstrate Hippo/YAP-TAZ pathway aberrations in many sarcomas, but this is among the first studies to demonstrate a well-defined oncogenic mechanism as the cause of Hippo pathway dysregulation.

Highlights

  • Uterine mesenchymal neoplasms afflict women across a wide age range

  • YWHAE-NUTM2 interacts with RAF1 and BRAF We investigated interaction of YWHAE-NUTM2 with

  • These studies demonstrated YWHAE-NUTM2 140/110 kDa isoform complexing with RAF1 and BRAF in ESS1 parental cells and in ESS1 expressing the YWHAENUTM2-FLAG construct (Fig. 1 and SFig. 1)

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Summary

Introduction

The biology of uterine neoplasms is heterogeneous, as exemplified by endometrial stromal sarcoma (ESS), which is the second most common subtype of malignant uterine mesenchymal tumor, after leiomyosarcoma[1]. There are no standardized therapies for any of the molecularly defined subtypes of ESS, underscoring the Endometrial stromal neoplasms comprise several clinicopathological entities, including endometrial stromal nodules, low-grade ESS (LG-ESS), high-grade ESS (HGESS), and undifferentiated uterine sarcoma. Endometrial stromal nodules and LG-ESS often contain oncogenic fusions of JAZF1 with polycomb genes, including SUZ12, PHF1, and EPC1, of which JAZF1-SUZ12 fusion is most common[3]. Oncogenic polycomb gene fusions are uncommon in HG-ESS, which instead often contain YWHAE-NUTM2 fusions or BCOR intragenic mutations[1,4]: these oncogenic somatic mutations are associated with aggressive clinical behavior and poor prognosis[5,6]. We previously identified translocation t(10;17)(q22;p13) as the mechanism of YWHAE-NUTM2 fusion in HG-ESS and we further showed the t(10;17) resulted in two alternative oncogenic fusions, which had been previously indistinguishable based on conventional chromosomal

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