PRAS40 Is a Functionally Critical Target for EWS Repression in Ewing Sarcoma

Lin Huang,Yuji Nakai,Ken Matsumoto,Iku Kuwahara

doi:10.1158/0008-5472.can-11-2254

Abstract

Ewing sarcoma family tumors (ESFT) are highly aggressive and highly metastatic tumors caused by a chromosomal fusion between the Ewing sarcoma protein (EWS) with the transcription factor FLI-1. However, expression of the EWS/FLI-1 chimeric oncogene by itself is insufficient for carcinogenesis, suggesting that additional events are required. Here, we report the identification of the Akt substrate PRAS40 as an EWS target gene. EWS negatively regulates PRAS40 expression by binding the 3' untranslated region in PRAS40 mRNA. ESFT cell proliferation was suppressed by treatment with an Akt inhibitor, and ESFT cell proliferation and metastatic growth were suppressed by siRNA-mediated PRAS40 knockdown. Furthermore, PRAS40 knockdown was sufficient to reverse an increased cell proliferation elicited by EWS knockdown. In support of a pathologic role for PRAS40 elevation in EFST, we documented inverse protein levels of EWS and PRAS40 in ESFT cells. Together, our findings suggest that PRAS40 promotes the development of ESFT and might therefore represent a novel therapeutic target in this aggressive disease.

Highlights

Ewing sarcoma is an aggressive and highly metastatic malignancy predominantly afflicting children and young adults
Ewing sarcoma family tumors (ESFT) cell proliferation was suppressed by treatment with an Akt inhibitor, and ESFT cell proliferation and metastatic growth were suppressed by siRNA-mediated PRAS40 knockdown
Ewing sarcoma protein (EWS)/FLI-1 alone was not sufficient to confer sarcomatous change in a transgenic mouse model [3]. These results indicated cellular context to be critical to the oncogenic potential of EWS/FLI-1 and additional events to be required for transformation to occur

Summary

Introduction

Ewing sarcoma is an aggressive and highly metastatic malignancy predominantly afflicting children and young adults. The ectopic expression of EWS/FLI-1 results in growth arrest or cell death rather than the promotion of cellular transformation in cells [1] and in mice [2]. EWS/FLI-1 alone was not sufficient to confer sarcomatous change in a transgenic mouse model [3]. These results indicated cellular context to be critical to the oncogenic potential of EWS/FLI-1 and additional events to be required for transformation to occur. These additional events may include deregulated p53 pathway [4] and loss of the p16 pathway [1].

Methods

Results

Conclusion