与尤因肉瘤断点蛋白EWS的相互作用定义了前列腺癌中重排的ETS因子的一种特定致癌机制。

An Interaction with Ewing's Sarcoma Breakpoint Protein EWS Defines a Specific Oncogenic Mechanism of ETS Factors Rearranged in Prostate Cancer.

作者信息

Kedage Vivekananda, Selvaraj Nagarathinam, Nicholas Taylor R, Budka Justin A, Plotnik Joshua P, Jerde Travis J, Hollenhorst Peter C

机构信息

Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN 47405, USA.

Medical Sciences, Indiana University School of Medicine, Bloomington, IN 47405, USA.

出版信息

Cell Rep. 2016 Oct 25;17(5):1289-1301. doi: 10.1016/j.celrep.2016.10.001.

DOI:10.1016/j.celrep.2016.10.001

PMID:27783944

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5123826/

Abstract

More than 50% of prostate tumors have a chromosomal rearrangement resulting in aberrant expression of an oncogenic ETS family transcription factor. However, mechanisms that differentiate the function of oncogenic ETS factors expressed in prostate tumors from non-oncogenic ETS factors expressed in normal prostate are unknown. Here, we find that four oncogenic ETS (ERG, ETV1, ETV4, and ETV5), and no other ETS, interact with the Ewing's sarcoma breakpoint protein, EWS. This EWS interaction was necessary and sufficient for oncogenic ETS functions including gene activation, cell migration, clonogenic survival, and transformation. Significantly, the EWS interacting region of ERG has no homology with that of ETV1, ETV4, and ETV5. Therefore, this finding may explain how divergent ETS factors have a common oncogenic function. Strikingly, EWS is fused to various ETS factors by the chromosome translocations that cause Ewing's sarcoma. Therefore, these findings link oncogenic ETS function in both prostate cancer and Ewing's sarcoma.

摘要

超过50%的前列腺肿瘤存在染色体重排，导致致癌性ETS家族转录因子异常表达。然而，区分前列腺肿瘤中表达的致癌性ETS因子与正常前列腺中表达的非致癌性ETS因子功能的机制尚不清楚。在此，我们发现四种致癌性ETS（ERG、ETV1、ETV4和ETV5），而非其他ETS，与尤因肉瘤断点蛋白EWS相互作用。这种EWS相互作用对于致癌性ETS功能（包括基因激活、细胞迁移、克隆存活和转化）是必要且充分的。值得注意的是，ERG的EWS相互作用区域与ETV1、ETV4和ETV5的该区域无同源性。因此，这一发现可能解释了不同的ETS因子如何具有共同的致癌功能。令人惊讶的是，EWS通过导致尤因肉瘤的染色体易位与各种ETS因子融合。因此，这些发现将前列腺癌和尤因肉瘤中的致癌性ETS功能联系了起来。