bims-myxlip 2022-04-10 papers

Issue of 2022–04–10
two papers selected by
Laura Mannarino, Humanitas Research

Neoplasia. 2022 Mar 30. pii: S1476-5586(22)00013-6. [Epub ahead of print]27 100784

Inhibition of HDACs reduces Ewing sarcoma tumor growth through EWS-FLI1 protein destabilization.

Gloria Pedot, Joana Graça Marques, Philip P Ambühl, Marco Wachtel, Stephanie Kasper, Quy A Ngo, Felix K Niggli, Beat W Schäfer.

Oncogenic transcription factors lacking enzymatic activity or targetable binding pockets are typically considered "undruggable". An example is provided by the EWS-FLI1 oncoprotein, whose continuous expression and activity as transcription factor are critically required for Ewing sarcoma tumor formation, maintenance, and proliferation. Because neither upstream nor downstream targets have so far disabled its oncogenic potential, we performed a high-throughput drug screen (HTS), enriched for FDA-approved drugs, coupled to a Global Protein Stability (GPS) approach to identify novel compounds capable to destabilize EWS-FLI1 protein by enhancing its degradation through the ubiquitin-proteasome system. The protein stability screen revealed the dual histone deacetylase (HDAC) and phosphatidylinositol-3-kinase (PI3K) inhibitor called fimepinostat (CUDC-907) as top candidate to modulate EWS-FLI1 stability. Fimepinostat strongly reduced EWS-FLI1 protein abundance, reduced viability of several Ewing sarcoma cell lines and PDX-derived primary cells and delayed tumor growth in a xenograft mouse model, whereas it did not significantly affect healthy cells. Mechanistically, we demonstrated that EWS-FLI1 protein levels were mainly regulated by fimepinostat's HDAC activity. Our study demonstrates that HTS combined to GPS is a reliable approach to identify drug candidates able to modulate stability of EWS-FLI1 and lays new ground for the development of novel therapeutic strategies aimed to reduce Ewing sarcoma tumor progression.

Keywords: EWS-FLI1; Ewing sarcoma; Fimepinostat; HDACi; Protein stability

DOI: https://doi.org/10.1016/j.neo.2022.100784

Mol Cell. 2022 Apr 04. pii: S1097-2765(22)00257-X. [Epub ahead of print]

The FUS::DDIT3 fusion oncoprotein inhibits BAF complex targeting and activity in myxoid liposarcoma.

Hayley J Zullow, Akshay Sankar, Davis R Ingram, Daniel D Samé Guerra, Andrew R D'Avino, Clayton K Collings, Rossana Lazcano, Wei-Lien Wang, Yu Liang, Jun Qi, Alexander J Lazar, Cigall Kadoch.

Mammalian SWI/SNF (mSWI/SNF or BAF) ATP-dependent chromatin remodeling complexes play critical roles in governing genomic architecture and gene expression and are frequently perturbed in human cancers. Transcription factors (TFs), including fusion oncoproteins, can bind to BAF complex surfaces to direct chromatin targeting and accessibility, often activating oncogenic gene loci. Here, we demonstrate that the FUS::DDIT3 fusion oncoprotein hallmark to myxoid liposarcoma (MLPS) inhibits BAF complex-mediated remodeling of adipogenic enhancer sites via sequestration of the adipogenic TF, CEBPB, from the genome. In mesenchymal stem cells, small-molecule inhibition of BAF complex ATPase activity attenuates adipogenesis via failure of BAF-mediated DNA accessibility and gene activation at CEBPB target sites. BAF chromatin occupancy and gene expression profiles of FUS::DDIT3-expressing cell lines and primary tumors exhibit similarity to SMARCB1-deficient tumor types. These data present a mechanism by which a fusion oncoprotein generates a BAF complex loss-of-function phenotype, independent of deleterious subunit mutations.

Keywords: ATP-dependent chromatin remodeling; BAF complex; CEBPB; FUS-DDIT3; MLPS; adipogenesis; enhancers; fusion oncoprotein; mesenchymal stem cells; myxoid liposarcoma

DOI: https://doi.org/10.1016/j.molcel.2022.03.019