The SWI/SNF ATPase BRG1 facilitates multiple pro-tumorigenic gene expression programs in SMARCB1-deficient cancer cells

Abstract

Malignant rhabdoid tumor (MRT) is driven by the loss of the SNF5 subunit of the SWI/SNF chromatin remodeling complex and then thought to be maintained by residual SWI/SNF (rSWI/SNF) complexes that remain present in the absence of SNF5. rSWI/SNF subunits colocalize extensively on chromatin with the transcription factor MYC, an oncogene identified as a novel driver of MRT. Currently, the role of rSWI/SNF in modulating MYC activity has neither been delineated nor has a direct link between rSWI/SNF and other oncogenes been uncovered. Here, we expose the connection between rSWI/SNF and oncogenic processes using a well-characterized chemical degrader to deplete the SWI/SNF ATPase, BRG1. Using a combination of gene expression and chromatin accessibility assays we show that rSWI/SNF complexes facilitate MYC target gene expression. We also find that rSWI/SNF maintains open chromatin at sites associated with hallmark cancer genes linked to the AP-1 transcription factor, suggesting that AP-1 may drive oncogenesis in MRT. Interestingly, changes in MYC target gene expression are not overtly connected to the chromatin remodeling function of rSWI/SNF, revealing multiple mechanisms used by rSWI/SNF to control transcription. This work provides an understanding of how residual SWI/SNF complexes may converge on multiple oncogenic processes when normal SWI/SNF function is impaired.

Emerging Themes in Mechanisms of Tumorigenesis by SWI/SNF Subunit Mutation

“…In agreement with this notion, we more recently discovered that inhibition of residual SWI/SNF function through acute degradation of BRG1 impairs MYC-target gene expression in rhabdoid tumor cells. 4 Taken together, these data reveal that there are at least 2 anti-MYC functions of SNF5, and show that residual SWI/SNF complexes in rhabdoid tumor cells actively support the pro-tumorigenic transcriptional functions of MYC ( Figure 4 ).…”

“… 3 Looking ahead, we discuss a promising new line of thinking in which mutations in SWI/SNF can also unleash the pro-tumorigenic potential of oncoprotein transcription factors like AP-1 and MYC. 4 Together, these emerging themes in SWI/SNF are beginning to expose the ways in which alterations to this macromolecular machine impact transcriptional regulatory networks to initiate, progress, and maintain the malignant state.…”

“…Our groups recently reported yet another connection between SWI/SNF and AP-1. 4 Seeking to understand how residual SWI/SNF complexes in rhabdoid tumor cells sustain oncogenic transcriptional events, we performed gene expression and chromatin accessibility profiling following acute depletion of BRG1. Despite the low levels of residual SWI/SNF complexes in these cells, 39 depletion of BRG1 reduces chromatin accessibility at more than 6000 sites across the genome, revealing that residual SWI/SNF complexes maintain chromatin accessibility even in the absence of SNF5.…”

Mutual Regulation of ncRNAs and Chromatin Remodeling Complexes in Normal and Pathological Conditions

“…Inhibition of the growth of rhabdoid tumors with lack of the SMARCB1, through knockdown of the SWI/SNF catalytic subunit SMARCA4, suggests that the survival of such tumor cells may depend on the residual activity of the SWI/SNF complex. This is confirmed by the existence of mutually exclusive subunits in SWI/SNF complexes [223]. As the ARID1A and ARID1B proteins are mutually exclusive in the SWI/SNF complex, it could be proposed that the survival of tumor cells with ARID1A mutations may depend on the presence of ARID1B in the residual SWI/SNF complex.…”

Targeting of the SWI/SNF chromatin remodeling complex in cancer therapy

“…Ингибирование роста рабдоидных опухолей с дефицитом SNF5 (SMARCB1), полученное с помощью нокдауна BRG1 (SMARCA4) каталитической субъединицы SWI / SNF, позволяет предположить, что выживание опухолевых клеток, дефицитных по SMARCB1, может зависеть от остаточной активности комплекса SWI / SNF. Это подтверждается существованием взаимоисключающих субъединиц, входящих в состав SWI / SNF [25]. Исходя из того, что белки ARID1A и ARID1B в комплексе SWI / SNF являются взаимоисключающими, выживание опухолевых клеток с мутациями ARID1A может зависеть от присутствия ARID1B в остаточном комплексе SWI / SNF.…”