SNF5/INI1 Deficiency Redefines Chromatin Remodeling Complex Composition during Tumor Development

Abstract

Malignant Rhabdoid Tumors (MRTs), a pediatric cancer that most frequently appears in the kidney and brain, generally lack SNF5 (SMARCB1/INI1), a subunit of the SWI/SNF chromatin-remodeling complex. Recent studies have established that multiple SWI/SNF complexes exist due to the presence or absence of different complex members. Therefore, the effect of SNF5 loss upon SWI/SNF complex formation was investigated in human MRT cells. MRT cells and primary human tumors exhibited reduced levels of many complex proteins. Furthermore, re-expression of SNF5 increased SWI/SNF complex protein levels without concomitant increases in mRNA. Proteomic analysis, using mass spectrometry, of MRT cells before and after SNF5 re-expression indicated the recruitment of different components into the complex along with the expulsion of others. IP-Western blotting confirmed these results and demonstrated similar changes in other MRT cell lines. Finally, reduced expression of SNF5 in normal human fibroblasts led to altered levels of these same complex members. These data establish that SNF5 loss during MRT development alters the repertoire of available SWI/SNF complexes, generally disrupting those associated with cellular differentiation. These findings support a model where SNF5 inactivation blocks the conversion of growth promoting SWI/SNF complexes to differentiation inducing ones. Therefore, restoration of these complexes in tumors cells provides an attractive approach for the treatment of malignant rhabdoid tumors. Implications SNF5 loss dramatically alters SWI/SNF complex composition and prevents formation of complexes required for cellular differentiation.

Composition and Function of Mutant Swi/Snf Complexes

“…Indeed, co-immunoprecipitation experiments from Ini1 (ySnf5) deficient tumor cells show that Brg1 (ySnf2) interacts with BAF180 (ySwi1) and Act6La (yArp7/yArp9), and loses its association with other members of the complex (e.g. our Snf5/Swi3 regulatory module) (Wei et al, 2014). By analogy, we purified an intact Snf2-Arp7-Apr9 complex with ySwi1 in the absence of Snf5.…”

Low-Dose Histone Deacetylase Inhibitor Treatment Leads to Tumor Growth Arrest and Multi-Lineage Differentiation of Malignant Rhabdoid Tumors

“…In particular, SMARCB1 is required in the SWI/SNF chromatin remodeling complex for controlling the differentiation potential of MRT cells (14)(15)(16). Furthermore, mounting evidence supports a role for SMARCB1 and functional chromatin remodeling complexes in cellular lineage commitment and differentiation, including myogenic (15,17), adipogenic (18), and erythropoietic (19) differentiation pathways.…”

The Chromatin-Modifying Protein HMGA2 Promotes Atypical Teratoid/Rhabdoid Cell Tumorigenicity

“…The hallmark alteration in AT/RT is the loss of the INI1 chromatin modifying protein, which may function to promote differentiation (5, 6). Maintenance of an undifferentiated state and persistence of factors that promote self-renewal, invasion, and proliferation likely contribute to AT/RT tumorigenicity.…”

“…Loss of the tumor suppressor INI1 blocks proper differentiation of neural stem and progenitor cells and is believed to be critical for the development of AT/RTs (6). Therapeutic failure in aggressive brain tumors such as AT/RTs is due to the lack of potency of existing agents, the impermeability of the blood-brain barrier, intratumoral and intertumoral heterogeneity, and activation of anti-apoptotic and metabolic programs that allow tumor cells to survive treatment (7, 8).…”