Biology subjects

Smith-Fry, K.

Publications and source records attributed to Smith-Fry, K..

4 recordsLinked to original sources

bioRxiv2026

BAF complex-independent gene activation by SS18::SSX

In synovial sarcoma, the BAF subunit SS18 is fused to SSX, a transcriptional repressor, generating the oncogenic SS18::SSX fusion protein. Incorporation of SS18::SSX into BAF complexes leads to their aberrant retargeting to Polycomb-repressed genes via SSX, while simultaneously altering their composition and activity. The presence of BAF at Polycomb target sites is widely assumed to be essential for gene activation. Here, we directly tested the requirement for BAF activity in synovial sarcoma cell survival and SS18::SSX-driven transcription. Using targeted degradation of BAF ATPase subunits and deletion of core components, we show that BAF loss has modest effects on sarcoma cell viability and does not impede SS18::SSX target gene expression. Consistently, deletion of the BAF ATPase subunit Smarca4 does not impair SS18::SSX-driven tumor formation in vivo. Using domain-specific SS18::SSX mutants, we further demonstrate that the fusion can activate oncogenic transcription independently of BAF interaction, and that this activity depends on the C-terminal QPGY-rich domain of SS18. Mechanistically, SS18::SSX promotes transcription by engaging the histone acetyltransferase EP300, independently of BAF. Accordingly, pharmacologic degradation of EP300/CREBBP suppresses SS18::SSX-driven transcriptional programs and impairs synovial sarcoma cell survival. Together, these findings challenge the view that BAF activity is required for SS18::SSX-mediated transcriptional activation and demonstrate that aberrant Polycomb target gene expression is sustained through recruitment of transcriptional coactivators in the absence of BAF. Our work reveals new therapeutic vulnerabilities in synovial sarcoma and suggests broader relevance for targeting coactivator-dependent transcription in fusion-driven cancers. HighlightsO_LIBAF degradation does not alter SS18::SSX-activated transcriptional programs C_LIO_LIDirect SS18::SSX transcriptional activation is independent of BAF interaction C_LIO_LIThe SS18 C-terminus engages the co-activator EP300 to promote gene expression C_LIO_LISmall molecule degraders of EP300/CREBBP abolish SS18::SSX-mediated transcription C_LI

cancer biology↗

bioRxiv2024

SS18::SSX redistributes BAF chromatin remodelers selectively to activate and repress transcription

Synovial sarcoma (SyS) is driven by the expression of a chromosomal translocation-generated SS18::SSX fusion oncoprotein1,2. This oncoprotein fuses the SSX carboxy terminal tail that binds ubiquitylated histone H2A (H2AK119ub)3-6 to the SS18 component of both canonical (CBAF) and non-canonical (GBAF, GLTSCR1-containing) BAF-family chromatin remodeling complexes7-11, wherein SS18::SSX reprograms the epigenetic landscape. Mice that express SS18::SSX develop tumors that faithfully recapitulate human SyS histopathologically and molecularly12-14, allowing dissection of transcriptional reprogramming in vivo15,16. Here, we show that SS18::SSX redistributes GBAF complexes broadly to promoters and distal enhancers decorated by H2AK119ub, which uncharacteristically lack the transcription-silencing trimethylation of H3K27 that otherwise accompanies H2AK119ub. Fusion-GBAF instead associates with H2AK119ub and transcription-enabling H3K4 trimethylation (promoters), monomethylation (distal enhancers), and H3K27 acetylation (both). CBAF with the fusion redistributes away from typical loci, avoids H2AK119ub-bearing regions, and instead narrowly flanks transcription start sites (TSSs), co-distributed with polybromo BAF (PBAF). Accelerated tumorigenesis in our SyS mouse model followed deletion of Smarcb1 (PBAF and CBAF), Pbrm1 (PBAF-specific), and Arid1a or Arid1b (CBAF-specific). While tumors lacking Arid1a or Arid1b retained SyS character, loss of Smarcb1 or Pbrm1 resulted in tumors lacking SyS features. These findings suggest that SyS transcriptional reprogramming includes both improper GBAF localization and gene activation at H2AK119ub-bearing regulatory regions and improper gene silencing through loss of CBAF.

cancer biology↗

bioRxiv2024

Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein. and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.

cancer biology↗

bioRxiv2023

ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97

The t(X,17) chromosomal translocation, generating the ASPSCR1-TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCC), frustrating efforts to identify therapeutic targets for these rare cancers. Proteomic analysis showed that VCP/p97, an AAA+ ATPase with known segregase function, was strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1-TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1-TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributed with ASPSCR1-TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrated the oncogenic transcriptional signature of ASPSCR1-TFE3, by facilitating assembly of higher-order chromatin conformation structures as demonstrated by HiChIP. Finally, ASPSCR1-TFE3 and VCP demonstrated co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCPs potential as a novel therapeutic target.

cancer biology↗