SYT-SSX1 (Synovial Sarcoma Translocated) Regulates PIASy Ligase Activity to Cause Overexpression of NCOA3 Protein

Yin Sun; Juanita Perera; Brian P. Rubin; Jiaoti Huang

doi:10.1074/jbc.M110.176693

SYT-SSX1 (Synovial Sarcoma Translocated) Regulates PIASy Ligase Activity to Cause Overexpression of NCOA3 Protein*

From the ^‡Department of Pathology and Laboratory Medicine,
^‖Jonsson Comprehensive Cancer Center, and
^**Broad Center for Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095,
the ^§Department of Biomedical Genetics, University of Rochester, Rochester, New York 14620, and
the ^¶Department of Anatomic Pathology and Molecular Genetics, Taussig Cancer Center and Lerner Research Institute, Cleveland Clinic Foundation, L25, Cleveland, Ohio 44195

2↵ To whom correspondence may be addressed. E-mail: yinsun{at}mednet.ucla.edu.
3↵ To whom correspondence may be addressed. E-mail: jiaotihuang{at}mednet.ucla.edu.

↵1 Current address: ZMBH-DKFZ Alliance, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany.

Abstract

Chromosomal translocations are a major source of genetic abnormalities causally linked to certain malignancies. Synovial sarcoma is an aggressive soft tissue tumor characterized by a chromosomal translocation between chromosome 18 and X, generating oncoproteins such as SYT-SSX1 and SYT-SSX2. The molecular mechanism underlying the oncogenic potential of SYT-SSX1/2 is not clear. Here we show that SYT-SSX1 leads to up-regulation of NCOA3, a protein critical for the formation of various cancers. The increase of NCOA3 is essential for SYT-SSX1-mediated synovial sarcoma formation. SYT-SSX1 does so by increasing the sumoylation of NCOA3 through interaction with a SUMO E3 ligase, PIASy, as well as the sumoylation of NEMO. NEMO has also been shown to physically interact with NCOA3. Increased sumoylation of NCOA3 leads to its increased steady state level and nuclear localization. Our findings represent the first example that an oncoprotein directly regulates substrate modification by a SUMO E3 ligase, and leads to overexpression of a protein essential for tumor formation. Such a mechanistic finding provides an opportunity to design specific therapeutic interventions to treat synovial sarcoma.

Footnotes

↵* This work was supported, in whole or in part, by National Institutes of Health Grant R01 CA093848 (to Y. S.). This work was also supported by Grants from the American Cancer Society (RSG-07-092-01-TBE), Dept. of Defense Prostate Cancer Research Program (PC061456), a developmental research award from UCLA SPORE in prostate cancer (PI: R. Reiter) and a challenge award from the Prostate Cancer Foundation (PI: O. Witte) (to J. H.).