The Oncoprotein SS18-SSX1 Promotes p53 Ubiquitination and Degradation by Enhancing HDM2 Stability

Abstract

Mutations of the p53 gene are uncommon in synovial sarcoma, a high-grade tumor genetically characterized by the chromosomal translocation t:(X;18), which results in the fusion of SS18 with members of SSX gene family. Although implicated in tumorigenesis, the mechanisms by which SS18-SSX promotes tumor growth and cell survival are poorly defined. Here, we show that SS18-SSX1 negatively regulates the stability of the tumor suppressor p53 under basal conditions. Overexpression of SS18-SSX1 enhanced p53 ubiquitination and degradation in a manner dependent on the ubiquitin ligase activity of HDM2. The negative effect of SS18-SSX1 expression on p53 was mediated by its ability to promote HDM2 stabilization through inhibition of HDM2 autoubiquitination. Furthermore, SS18-SSX1 expression altered the induction of p53-regulated genes in response to cellular stress by abrogating the transactivation of HDM2, PUMA, and NOXA but not p21. Our data uncover a novel mechanism whereby SS18-SSX1 can negatively regulate p53 tumor-suppressive function by increasing the stability of its negative regulator HDM2 and suggest that chemical compounds that target the p53-HDM2 regulatory axis may be of therapeutic benefit for the treatment of synovial sarcoma.

p53 expression in synovial sarcoma and its association with prognostic factors

“…Characteristics of the subjects were similar to those reported by Oda et al 8 In this study, the tumor was found at the extremity, head Some cases expressing p53. This result was similar to that reported by Oda et al 8 and Schneider-Stock et al 11 In synovial sarcoma, p53 should decreases as reported by D'Arcy et al 4 , though the soft tissue tumors may have increased expression of p53 and this is associated with poor prognosis. 12 Several processes can increase p53 expression such as telomere shortening, DNA damage, oxidative stress, oncogenic stress and Ras activation.…”

“…Moreover, SYT-SSX1 shows pro-survival activity and increases cell growth. 4 p53 plays important role to maintain genome integrity. Upon DNA damage, the p53 will be activated.…”

Loss of SS18-SSX1 Inhibits Viability and Induces Apoptosis in Synovial Sarcoma

“…Previous studies by Peng et al [29] demonstrated a reduction in antiapoptotic gene B-cell lymphoma-2 (bcl-2) and a parallel increase in proapoptotic caspase-3 after knockdown of SS18-SSX by siRNA. In addition, D'Arcy et al demonstrated expression of SS18-SSX1 in U2OS osteosarcoma cells inhibited apoptosis induced by cytotoxic agents such as doxorubicin [10]. We have validated that in our cell models SS18-SSX1 reduction is also linked to apoptosis activation.…”

Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 Targets MDM2 To Deregulate the p53 Tumor Suppressor Pathway

“…First, MDM2 stabilizes its own protein levels through posttranslational modifications, such as sumoylation and phosphorylation. Sumoylation protects MDM2 from proteasomal degradation by competing with ubiquitin at its major conjugation site, Lys 464 (4), while the phosphorylation of MDM2 prevents it from self-ubiquitination, thereby stabilizing MDM2 (9,11). Second, the deubiquitination enzymes HAUSP and USP2a have been shown to directly bind and remove ubiquitin molecules from MDM2, resulting in its stabilization (2,26,41).…”