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YWHAE-NUTM2 oncoprotein regulates proliferation and cyclin D1 via RAF/MAPK and Hippo pathways.

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.

SUBMITTER: Ou WB

PROVIDER: S-EPMC8097009 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Accumulating evidence has indicated that aberrant expression of long non-coding RNAs (lncRNAs) is an important oncogenic factor. The aim of the present study was to investigate the role of LINC01296, an lncRNA that exerts a tumor?promoting function in many cancers, in the regulation of proliferation, metastasis and the cell cycle of osteosarcoma. The expression of LINC01296 in osteosarcoma tissues and adjacent healthy tissues of 30 patients was analyzed by quantitative real?time PCR (qRT?PCR). The relationship between LINC01296 expression and the survival of patients with osteosarcoma was also explored. The expression levels of LINC01296 in osteosarcoma cells and normal cells were compared. LINC01296 knockdown and overexpression were performed in MG63 and HOS8603 osteosarcoma cells by transfecting LINC01296 shRNA and an expression plasmid respectively, followed by investigation of the changes on cell proliferation, migration, apoptosis and cell cycle arrest. Western blotting was used to analyze the changes of cell cycle regulators. Cyclin D1 knockdown and overexpression were carried out to verify the interaction between LINC01296 and cyclin D1. LINC01296 overexpression was demonstrated as a biomarker of osteosarcoma, which was closely correlated with the poor survival of patients with osteosarcoma. A high expression of LINC01296 was observed in osteosarcoma cells, which was closely associated with enhanced proliferation, invasion, and migration of osteosarcoma cells. Cyclin D1 expression was positively correlated with the expression of LINC01296 in osteosarcoma cells. Cyclin D1 knockdown or overexpression played a deterministic role in mediating the effect of LINC01296 on osteosarcoma cells. LINC01296 is an oncogenic lncRNA in osteosarcoma. The proliferation, invasion and migration of osteosarcoma cells could be effectively retarded by inhibition of LINC01296. The cancer?promoting effect of LINC01296 on osteosarcoma was determined by cyclin D1.

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YWHAE-NUTM2 oncoprotein regulates proliferation and cyclin D1 via RAF/MAPK and Hippo pathways.

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