Abstract
This study demonstrates deregulation of polycomb activity by the synovial sarcoma-associated SYT-SSX2 oncogene, also known as SS18-SSX2. Synovial sarcoma is a soft tissue cancer associated with a recurrent t(X:18) translocation event that generates one of two fusion proteins, SYT-SSX1 or SYT-SSX2. The role of the translocation products in this disease is poorly understood. We present evidence that the SYT-SSX2 fusion protein interacts with the polycomb repressive complex and modulates its gene silencing activity. SYT-SSX2 causes destabilization of the polycomb subunit Bmi1, resulting in impairment of polycomb-associated histone H2A ubiquitination and reactivation of polycomb target genes. Silencing by polycomb complexes plays a vital role in numerous physiological processes. In recent years, numerous reports have implicated gain of polycomb silencing function in several cancers. This study provides evidence that, in the appropriate context, expression of the SYT-SSX2 oncogene leads to loss of polycomb function. It challenges the notion that cancer is solely associated with an increase in polycomb function and suggests that any imbalance in polycomb activity could drive the cell toward oncogenesis. These findings provide a mechanism by which the SYT-SSX2 chimera may contribute to synovial sarcoma pathogenesis.
Highlights
The manipulation of chromatin organization is at the heart of a plethora of biological processes
They were originally identified in Drosophila as repressors of Hox genes for posterior body segmentation [2]. polycomb complexes are classically divided into Polycomb Repressive Complex 1 (PRC1) and Polycomb Repressive Complex 2 (PRC2) [1]
Using a retroviral system that allowed expression of SYT-SSX2 in U2OS cells at levels similar to those detected in primary synovial sarcoma cells (Syn1 cells- Figure 1A; in synovial sarcoma, SYT-SSX2 expression is driven by the robustly active promoter of SYT), we were able to detect substantial colocalization of SYT-SSX2 with the polycomb protein Bmi1 (Figure 1B)
Summary
The manipulation of chromatin organization is at the heart of a plethora of biological processes. PcG complexes are implicated in the repression of gene transcription through exquisite modulation of chromatin structure. They were originally identified in Drosophila as repressors of Hox genes for posterior body segmentation [2]. Polycomb silencing plays an important role in cell fate determination, self-renewal in both embryonic and adult stem cells, as well as X-chromosome inactivation [1]. These processes result from polycomb suppression of key developmental pathways, including Wnt and Notch [9,10,11]
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