Subunits of SWI/SNF chromatin remodeling complexes are specifically mutated in a variety of cancers. Specific biallelic inactivation of the core SWI/SNF subunit SNF5 (also known as SMARCB1, INI1 and BAF47) is present in 98% of malignant rhabdoid tumors (RT).1,2 RT are aggressive cancers that are poorly differentiated, locally invasive, frequently metastatic and highly lethal. SNF5 mutation has also been implicated in a familial cancer predisposition syndrome as well as in the genesis of familial schwannomatosis, multiple meningiomas, epithelioid sarcomas and extraskeletal myxoid chondrosarcomas.3-7 Recently, additional SWI/SNF subunits, including ARID1A (BAF250A), PBRM1 (BAF180) and BRG1, have been found to be specifically mutated at high frequency in subsets of ovarian, kidney and lung cancers, further demonstrating a broad role for SWI/SNF complexes in tumor suppression.8-12 Consequently, elucidation of the mechanisms that drive formation of these cancers is of great interest.
SWI/SNF complexes occupy a key position at the intersection between epigenetic regulation and tumor suppression. These evolutionarily conserved complexes utilize the energy of ATP hydrolysis to mobilize nucleosomes, remodel chromatin and regulate transcription of numerous target genes. Transcriptional regulation by SWI/SNF complexes has been implicated in the balanced control of proliferation and differentiation in multiple tissues.13,14 Mammalian SWI/SNF complexes are comprised of a SWI2/SNF2 family ATPase (either BRG1 or BRM), common core subunits (SNF5, BAF155 and BAF170) and 4–8 additional subunits that vary by cellular lineage, including ARID1A/BAF250A and PBRM1/BAF180.13,14 Mouse models have revealed a potent and specific role for SNF5 as a tumor suppressor. Heterozygous mice are prone to developing RT, and conditional, biallelic inactivation leads to a mixture of lymphomas and RT in 100% of mice with a median onset of only 11 weeks.15-18 Snf5-deficient murine tumors develop with remarkable rapidity in comparison to mice with mutations of other tumor suppressors such as p53 (20 weeks), p19ARF (38 weeks) or p16Ink4a (60 weeks), thus indicating an essential role for SNF5 in suppressing cancer.19-21
Recent evidence suggests that epigenetically driven changes in gene expression may drive tumorigenesis following SNF5 inactivation. Despite their aggressive nature, RT are diploid, and, aside from loss of SNF5 itself, the large majority are indistinguishable from normal cells on high-density SNP arrays.22 The dysfunctional epigenetic state caused by SNF5 loss occurs in part due to disrupted epigenetic antagonism between SWI/SNF and Polycomb complexes.23 The altered epigenetic landscape that arises following SNF5 loss promotes the transcriptional activation of several oncogenes (c-MYC, CCND1, GLI1, AURKA), which have been identified as SNF5 targets and are upregulated in SNF5-deficient tumors.22,24-27 The tumor suppressor p16INK4A is also regulated by SNF5 in RT cell lines and mouse embryonic fibroblasts, although it remains to be shown whether p16INK4A silencing is common in primary RT.23,28,29 Thus, tumor suppressors epigenetically inactivated in cancers following SNF5 loss have remained elusive.
The BIN1 (bridging integrator 1/box-dependent Myc interactor 1/amphyphysin II) gene encodes a collection of approximately 10 alternatively spliced SH3 adaptor proteins, which have varied expression patterns and subcellular localization.30 Several lines of evidence indicate that BIN1 exhibits tumor suppressor activity. BIN1 isoforms can inhibit cellular transformation by the K-RAS, C-MYC and E1A oncogenes or by dominant-negative p53.31 This inhibition may be mediated by physical associations between BIN1 and MYC or the RAS-specific guanine nucleotide exchange factors SOS-1 and SOS-2, which may function to inhibit MYC-induced gene activation and limit invasiveness of RAS-dependent cancers, respectively.32-35 Furthermore, Bin1 mutant mice are cancer prone, and Bin1 deficiency has also been shown to play an important role in the ability of cancer cells to avoid detection and destruction by the immune system.36,37
Interestingly, loss of BIN1 expression without genetic mutation has been observed in several human cancers, suggesting the mechanism of inactivation may primarily be epigenetic.31,38,39 Promoter hypermethylation or aberrant splicing have been suggested as possible causes for BIN1 downregulation, but a mechanism for cancer-specific BIN1 suppression is largely unclear.38,40 In this study, we provide evidence that BIN1 is a novel SNF5 target whose epigenetic deregulation drives proliferation of SNF5-deficient tumor cells. Identification of aberrant epigenetic silencing of BIN1 as a conserved event in SNF5-deficient cancers illustrates how changes in target gene expression due to aberrant chromatin remodeling complex activity can drive rapid tumorigenesis.
SNF5-deficient RT are almost exclusively diploid and genomically stable and lack recurrent genetic abnormalities on SNP arrays other than at the SNF5 locus. Rather, deregulation of expression of known SNF5 targets, such as CCND1, GLI1, RHOA, AURKA and c-MYC, without evidence of genetic amplification suggests that epigenetically based alteration of gene expression is a key mechanism of SNF5-mediated tumor suppression.22,24-27,43,44 SWI/SNF complexes are specifically enriched at promoters, where they contribute to chromatin remodeling that facilitates epigenetic control of gene expression.45 Thus, defective remodeling, perhaps akin to “epigenetic instability,” caused by SNF5 loss could conceivably deregulate many target genes and activate pathways that cooperatively drive cancer growth, thus amplifying the effects of inactivation of a single gene and providing an explanation for the rapid tumorigenesis caused by SNF5 loss.22,46 In this study, we show that aberrant silencing of BIN1 is a direct effect of SNF5 loss in primary human RT of brain and kidney, murine Snf5-deficient lymphoma as well as cell culture models of RT, and that loss of BIN1 expression is required for the proliferation of SNF5-deficient tumor cells. Our data supports a model in which SNF5 is required for normal expression of BIN1 via recruitment of SWI/SNF chromatin remodeling activity to the BIN1 promoter. This is consistent with data from a recent genome-wide study of SWI/SNF localization in human cells, which showed SNF5 occupancy throughout the BIN1 promoter.45 Consequently, in the absence of SNF5, BIN1 expression is silenced.
Several lines of evidence indicate that negative regulation of MYC represents a major aspect of BIN1-mediated tumor suppression. BIN1 inhibits MYC-induced gene activation in vitro and is required for apoptosis caused by MYC overexpression.33,47 BIN1 and MYC physically interact, and their levels are inversely correlated, suggesting that BIN1 may affect MYC expression or protein stability.33,34 Further, forced expression of BIN1 selectively reduces colony formation in neuroblastoma cell lines with multiple copies of N-MYC, suggesting selective pressure for BIN1 inactivation in tumors driven by MYC.48 This is consistent with our observations of specific BIN1 downregulation and MYC overexpression in SNF5-deficient tumors compared with other tumor types.22 Furthermore, like BIN1, SNF5 has also been shown to regulate MYC target activation, and SNF5 and BIN1 were identified as two of only 17 genes whose knockdown overrides MYC-dependent oncogene-induced senescence driven by constitutive BRAF activation.49-51 Collectively, these data suggest that SNF5 and BIN1 may act in a common pathway in which SNF5 controls the expression of the effector BIN1. This is supported by gene expression studies in a murine model of muscle differentiation, in which induction of Bin1 by the myogenic transactivator MyoD is blocked by a dominant-negative SWI/SNF ATPase.52
The fact that expression of BIN1 is attenuated in human cancer without frequent genetic mutation underscores both the importance of BIN1 activity in tumor suppression and the potential impact of epigenetic deregulation of gene expression in cancer.39 Given our previously published work demonstrating that SNF5-deficient RTs are genomically stable, and that transcriptional deregulation of target genes is associated with the RT phenotype, identifying SNF5 targets provides insight into the mechanisms driving the proliferation of these cancers and suggests potential novel therapeutic targets. It is interesting to note that BIN1 has been implicated in the regulation of other targets reported to be regulated by SNF5. For example, BIN1 is a known negative regulator of c-MYC, a proliferation-promoting gene upregulated in RT. Additionally, BIN1 has been shown to genetically interact with Rho GTPases and could conceivably contribute to the increased Rho activity observed in RT cells.44,52,53 Finally, while the cellular function of BIN1 is not completely understood, its ability to interact with many binding partners through its SH3 domain and its ability to translocate to the nucleus suggests that BIN1 may be an example of a bridge between epigenetic gene regulation and transduction of multiple types of extracellular signals.30,54,55 Disruption of such coordinated signaling activity following SNF5 loss would be analogous to our finding that upstream control of Hedgehog signaling becomes uncoupled from Hedgehog target gene transcription in the absence of SNF5, collectively raising the possibility of a role for SNF5 in coordinated transduction of lineage-specific growth and differentiation signaling, an area for future investigations.24,56
Identification of BIN1 as a SNF5 target gene whose downregulation promotes the genesis of SNF5-deficient tumors may also have implications for the treatment of these aggressive cancers. For example, the gene indoleamine-2,3-dioxygenase (IDO) is an immunomodulatory enzyme constitutively overexpressed in many human tumors, whose elevation can promote evasion of immune surveillance by tumors. Ido is regulated by BIN1 in mice and is required for immune escape by MYC/HRAS-transformed Bin1-deficient primary cells. An orally bioavailable IDO inhibitor was found to potentiate the effects of several chemotherapeutic agents in a BIN1-deficient breast cancer mouse model.37 Additionally, BIN1 has recently been implicated in the negative regulation of the DNA repair enzyme PARP1.57 Unrestrained PARP1 activity in the absence of BIN1 leads to increased DNA repair capacity and resistance to chemotherapeutic agents, which would be consistent with the lack of DNA damage sensitivity in Snf5-deficient cells.22,57 Given that BIN1 is silenced following SNF5 loss, existing IDO and PARP inhibitors already in clinical trials are worthy of evaluation in SNF5-deficient cancer models.
Identification of BIN1 as a SNF5 target gene silenced in RT constitutes a novel mechanism of tumor suppression and demonstrates the potential of mining cancer transcriptomes to establish novel pathways that would not otherwise be identified by sequencing of cancer genomes. Integration of genome-wide expression data with epigenomic analyses will provide crucial insight into the contributions of alterations of the chromatin landscape to transcriptional programs that promote oncogenesis. SNF5-deficient tumors represent a useful system in which to initiate such studies, given that they are diploid, appear genomically stable and are initiated by mutation of a chromatin regulator. As mutations in other SWI/SNF subunits have recently been found at high frequency in several other types of human cancer, it will be important to determine whether these cancers are driven by deregulation of similar pathways.
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