Synovial sarcoma is a gateway to the role of chromatin remodeling in cancer

Abstract

Patients afflicted with synovial sarcoma share the fate of other translocation positive sarcomas; the driver mutation for this cancer is known, yet no means to target the fusion protein SS18-SSX directly exist. Current chemotherapeutic regimens are minimally beneficial, particularly in patients with metastatic disease. SS18-SSX putatively promotes its oncogenic activity through protein-protein interactions that alter genetic programs through chromatin remodeling. This review discusses the functional protein network of SS18-SSX, both wild-type and fusion protein, considers its intrinsically disordered nature, and provides insights into potential therapeutic strategies. A comprehensive overview of the clinical characteristics reveals the need for newly targeted therapeutics based upon oncogenic transformation by the fusion protein SS18-SSX. The wild-type, non-fused proteins SS18 and SSX are presented including their molecular structure and biological function with regard to protein-protein interactions. The interactions of the wild-type proteins inform the oncogenic changes of the fusion protein. The SS18-SSX fusion protein and its protein interactions are described and evaluated for their biological consequences that lead to oncogenesis. This review illustrates the key protein interactions of SS18-SSX that may qualify as primary targets for small molecule-based disruption leading to the development of SS18-SSX-specific drugs. These novel targeted therapeutics may provide a specificity that ultimately improves survival while reducing morbidity of patients with synovial sarcoma.

Novel and divergent genes in the evolution of placental mammals

“…For example, several autosomal PRD class homeobox gene families (ARGFX, DPRX, TPRX, LEUTX, CPHX) and one autosomal ANTP class homeobox gene (NANOGNB) have previously been noted to be specific to placental mammals and expressed in pre-implantation development [17,[26][27][28][29]; three of these, LEUTX, CPHX and NANOGNB, were identified in the present study. Additional placental mammal-specific genes we identified with enriched expression in preimplantation embryos include: ZSCAN4, implicated in pluripotency [30,31] and two members of an extended gene family KHDC1 and DPPA5 [32] which have been previously reported as mammal-specific; and a related group of transcriptional repressors, SSX1-5, which are frequently over-expressed in cancer with reported roles in cell adhesion and migration, cancer stem cell generation and chromatin remodelling [33][34][35][36]. These data imply that during the evolution of eutherian mammals there was extensive remodelling of genetic pathways controlling formation of the blastocyst.…”

Proteomic signatures corresponding to the SS18/SSX fusion gene in synovial sarcoma

“…Several recent reports have suggested that SS is most likely derived from primitive mesenchymal cells that undergo differentiation [30–33]. In addition, regarding the primitive origin of SS, the expression of human SS18-SSX2 fusion protein within myoblasts in transgenic mouse model was shown to produce tumors similar to human SSs [31, 13, 34]. These present and previous findings suggest that SS18/SSX might suppress smooth muscle differentiation, while offering clues to the cellular origin and real differentiation of SS.…”

Biphasic axillary synovial sarcoma diagnosed by preoperative fine‐needle aspiration cytology

“…Approximately two‐thirds of SS show SSX1 and one‐third of SS show SSX2 fusions, which are believed to be mutually exclusive. SSX4 gene is rarely involved . It must be taken into account that molecular studies must be complemented with cytological, histological, and immunohistochemical data.…”