A First-of-its-Kind Discovery published on Mol Cancer by the Pei Duanqing Team at Westlake University

Nuclear condensates are known to regulate cell fate control, but their role in oncogenic transformation remains largely unknown.

On April 27, 2024, a collaborative research team led by Pei Duanqing from Westlake University, Baojian Liao from the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Jin Wang from Sun Yat-sen University, and Micky D. Tortorella from the Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, published an article titled "Exclusion of HDAC1/2 complexes by oncogenic nuclear condensates" in Molecular Cancer (IF=37). This study demonstrates how oncogenic potential can be acquired through condensate reshaping. The oncogene SS18 and its fusion counterpart SS18-SSX1 both form condensates, but they exhibit distinct properties and impacts on three-dimensional genome structure.

Cancerous condensates, rather than their wild-type counterparts, readily exclude HDAC1 and 2 complexes. This exclusion allows abnormal accumulation of H3K27ac at chromatin sites, leading to oncogenic expression of crucial target genes. These findings provide the first evidence of condensate reshaping as a transformative event in the genesis of oncogenes and suggest that these condensates could be targeted for therapeutic intervention.

Oncogenes undergo mutations to become oncogenic. For instance, RAS becomes oncogenic through a V12 point mutation. Chromosomal translocations are a common mechanism leading to dysregulation of kinases and transcription factors. Based on these transformative events, successful therapeutic approaches have been developed. For example, the Philadelphia chromosome, carrying a translocation between chromosomes 22 and 9, generates BCR-Abl, which has been successfully targeted by Gleevec.

Biomolecular condensates formed through liquid-liquid phase separation (LLPS) are ubiquitous in cells and play pivotal roles in diverse biological processes, including gene transcription regulation, innate immunity, and neuronal transmission. The fundamental principle of condensate formation relies on multivalent interactions between macromolecules, such as DNA/RNA molecules and proteins composed of multiple interaction domains and/or intrinsically disordered regions (IDRs). Recent studies suggest that LLPS condensates may play a crucial role in tumorigenesis. Furthermore, recent research has proposed another mechanism, namely low-affinity interactions with spatially clustered binding sites (ICBS), which also contribute to condensate formation and can be distinguished by half-FRAP.

Synovial sarcoma, a malignant tumor primarily affecting adolescents and young adults, constitutes 8-10% of soft tissue malignancies. Nearly all synovial sarcomas carry a chromosomal translocation, t (X,18;p11, q11), resulting in the fusion protein SS18-SSX. This fusion protein arises from the replacement of the 8 C-terminal amino acids of the SS18 protein encoded by chromosome 18 with the C-terminus of the SSX gene family from chromosome X (mostly SSX1, less frequently SSX2, and rarely SSX4). Studies have demonstrated that the SS18-SSX fusion protein, by recognizing the H2AK119ub histone modification and hijacking the BAF and PRC1.1 complexes, is necessary and essential for the development of synovial sarcoma.

The SS18 protein regulates pluripotent stem cell conversion (PST) through a tyrosine-based phase separation mechanism. Intriguingly, the oncogenic fusion SS18-SSX protein also forms condensates. The mechanism by which SS18-SSX condensates acquire oncogenic activity remains unclear. This study found that tumor condensates formed by SS18-SSX physically exclude HDACs, allowing abnormal accumulation of H3K27ac at new target sites.