Oncogene (2014) 33, 2681–2689 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc

REVIEW The SWI/SNF genetic blockade: effects in cell differentiation, cancer and developmental diseases

OA Romero and M Sanchez-Cespedes

Our rapidly growing knowledge about cancer genetics attests to the widespread occurrence of alterations at encoding different components of the SWI/SNF complex. This reveals an important new feature that sustains cancer development: the blockade of remodeling. Here, we provide an overview of our current knowledge on the alterations of chromatin-remodeling factors, and how they relate to cancer and human developmental diseases. We also consider the functional repercussions, particularly how the inactivation of the SWI/SNF complex impairs the appropriate cell response to nuclear signaling, which, in turn, prevents cell differentiation and sustains independently of the environment.

Oncogene (2014) 33, 2681–2689; doi:10.1038/onc.2013.227; published online 10 June 2013 Keywords: SWI/SNF; ; BRG1; ; cancer; cell differentiation

THE SWI/SNF COMPLEX: TYPES AND COMPOSITION the epigenetic transcriptional repressor complexes NcoR and 2 Chromatin-remodeling complexes act in healthy adult tissues mSin3A/HDAC. during embryonic development and in cell differentiation processes to facilitate the access of multiple factors to the regulatory regions of target genes.1 On the basis of the GENE ALTERATIONS IN COMPONENTS OF CHROMATIN- identity of their catalytic subunit, four families of ATP-dependent REMODELING COMPLEXES ARE COMMON IN HUMAN CANCER chromatin-remodeling complexes have been described: SWI/SNF, More than 10 years have passed since inactivating mutations at 2,3 INO80/SWR1, ISWI and NURD. In the present review, we will SMARCB1 (henceforth SNF5) were first reported in human cancer, focus on the SWI/SNF, a particular complex that is powered by linking chromatin remodeling and cancer development.6 As a either of two alternative ATPases, BRM and BRG1, which catalyze bona fide tumor-suppressor gene, SNF5 is biallelically inactivated the complex-remodeling capability. BRG1 and BRM are highly in human tumors. Most mutations predict truncated and homologous and have similar domains: the QLQ domain for are mainly found in malignant rhabdoid tumors (MRTs), a pediatric –protein interaction, the HSA domain (containing a and highly lethal form of cancer that arises primarily in kidney and domain associated with a SANT DNA-binding domain), brain. SNF5 inactivation can also be found in choroid plexus the ATPase domain and the bromodomain, through which the carcinomas and in rare cases of pediatric brain tumors.7 2 two proteins recognize acetylation marks on histone tails. The mutations arise either somatically or in the germ line Two SWI/SNF multiprotein complexes have been described in conferring, in the latter case, a cancer predisposition syndrome.6 mammals, the BRG1-associated factors (BAF), also called Alongside SNF5, mutations in SMARCA4 (henceforth BRG1) were SWI/SNF-a, and the polybromo-BRG1-associated factors, also identified a few years later in different types of cancer cell line8,9 known as SWI/SNF-b. The complexes share a number of and in lung primary tumors10,11 (Figure 1). In a screening of proteins, such as BAF170, BAF155, BAF60a/b/c, BAF57, BAF53a/b, lung cancer cell lines, BRG1 inactivation was found to affect more BAF47, BAF45a/b/c/d and b-actin, while differing with respect than a quarter of non-small cell lung cancer lines. This is the fourth 4,5 to other components. For example, the a-complex includes the most commonly altered gene in this type of lung cancer after associated members BAF250a and BAF250b, which are inter- TP53, CDKN2A and LKB1.12 In 2006, Kiskinis et al.13 reported the 4,5 changeable and not present simultaneously in the complex. By presence of an inactivating mutation in another core member of contrast, the b-complex contains up to three additional members: the SWI/SNF complex, the SMARCE1 (encoding the BAF57 protein), 4,5 the BAF180, BAF200 and BRD7 proteins. However, the main in a breast cancer cell line, and, 2 years later, inactivation at PBRM1 difference between the SWI/SNF complexes is the ATPase. (encoding the BAF180) was also detected in breast cancer.14 Although this can be either BRG1 or BRM in the SWI/SNF-a,itis Around the same time, ARID1A, another SWI/SNF component, only BRG1 in the SWI/SNF-b. was found to be altered in a lung cancer cell line, a breast Although the focus of this review is the SWI/SNF complex, it primary tumor and in ovarian carcinomas.15,16 More recently, the should be borne in mind that the picture is greatly complicated latest generation-sequencing technologies have extended these by the participation of BRG1 and other SWI/SNF components in findings to other tumor types, such as PBRM1 in kidney carci- epigenetic complexes other than the SWI/SNF. Among these are nomas or ARID1A (encoding BAF250a) in bladder cancer.17,18 It is the chromatin-remodeling complexes WINAC and NUMAC, and worth to mention here that the mutations at ARID1A and PBRM1 in

Genes and Cancer Group, Cancer Epigenetics and Biology Program—PEBC, Bellvitge Biomedical Research Institute—IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. Correspondence: Dr M Sanchez-Cespedes, Genes and Cancer Group, Cancer Epigenetics and Biology Program—PEBC, Bellvitge Biomedical Research Institute—IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain. Email: [email protected] Received 20 February 2013; revised 17 April 2013; accepted 17 April 2013; published online 10 June 2013 The SWI/SNF genetic blockade OA Romero and M Sanchez-Cespedes 2682

Figure 1. Components of the SWI/SNF complex that have been found to be mutated in cancer and the type of cancer carrying mutations at each subunit. The corresponding reference is indicated in parentheses.

ovarian and kidney malignancies, respectively, are mainly found in PHENOTYPES ASSOCIATED WITH GERM-LINE ALTERATIONS clear cell carcinomas. This evidences a specific clustering of the AT CHROMATIN REMODELERS: HUMAN SYNDROMES AND alterations at these two components of the SWI/SNF complex in MOUSE MODELS histopathological subtypes. Furthermore, these technologies have Most known tumor-suppressor genes are associated with cancer- revealed that other components of chromatin-remodeling related syndromes. These syndromes are caused by a germ-line complexes, or factors closely related to them, are mutated in mutation, either inherited or arising de novo, in one of the cancer, such as ARID1B (encoding BAF250b) and ARID2 (encoding two alleles of the tumor-suppressor gene and conferring BAF200) (Figure 1). The list continues to grow and Figure 1 a predisposition to develop cancer. Intriguingly, in the case of provides a summary of the SWI/SNF-related proteins that are chromatin-remodeling components, in addition to cancer predis- known to be genetically inactivated in human cancer, updating position, germ-line mutations at some of these genes cause 5 that of a previous review. It has to be taken into account that the developmental autism-related diseases. evidences of genetic inactivation in genes encoding chromatin- remodeling factors are recent and that most data comes from deep sequencing technologies applied to whole genome Germ-line mutations in SWI/SNF components and cancer or to exomes, a type of approach that lead to a certain amount of predisposition false negative results. Therefore, efforts in individual sequencing A strong indicator of the participation of chromatin-remodeling of each gene, combined with approaches to accurately complexes in cancer development is their association with a detect intragenic homozygous deletions in tumor-suppressor predisposition to develop cancer in the form of cancer-related genes, are required to definitely determine the precise syndromes, in humans, and in mouse genetic models. In this frequency of alterations at these genes, in the distinct types regard, the SNF5 gene is biallelically inactivated in MRTs of tumors. somatically and in the germ line, causing the so-called rhabdoid In addition to mutations in genes coding for proteins predisposition syndrome.7 Individuals with this syndrome are of the SWI/SNF complex, mutations of components of other predisposed to having renal or extrarenal MRTs, and a variety of chromatin-remodeling complexes or of factors controlling tumors of the central nervous system, including choroid chromatin marks, such as EP300 or CREBBP, have been found in plexus carcinoma, medulloblastoma and central primitive cancer.19,20 However, this specific subject is not covered in neuroectodermal tumors (Table 1). Furthermore, germ-line muta- the present review. tions at SNF5 are associated with schwannomatosis, a rare

Oncogene (2014) 2681 – 2689 & 2014 Macmillan Publishers Limited The SWI/SNF genetic blockade OA Romero and M Sanchez-Cespedes 2683 Table 1. Diseases and cancer predisposition syndromes in mice and human individuals with germ-line mutations at SWI/SNF genes

Gene Homozygous mice Heterozygous mice Human Human (protein) Cancer predisposition Cancer predisposition Autism-related Brain abnormalities syndrome

SMARCB1 Embryonic lethal Malignant rhabdoid tumors23 Malignant rhabdoid tumor7 Coffin–Siris32 (SNF5) Familial schwannomatosis22 Others: BAF47 INI1 SMARCA4 Embryonic lethal Mammary epithelial tumors. Malignant rhabdoid tumor Coffin–Siris24 (BRG1) Lung tumors on ethyl carbamate predisposition24 Others: treatment. BAF190 Exencephaly25,26,27 SMARCE1 ND ND Multiple spinal meningiomas105 Coffin–Siris32 (BAF57) PBRM1 Embryonic lethal Indistinguishable from (BAF180) wild-types103 ARID1A ND ND Coffin–Siris32 (BAF250A) Other SMARCF1 ACTL6B Neural developmental Indistinguishable from (BAF53b) abnormalities wild-types104 ARID1B ND ND Coffin-Siris31,32 (BAF250b) Intellectual disability106 SMARCC1 Embryonic lethal Exencephaly67 (BAF155) SMARCA2 Heavier than littermates- Indistinguishable from Coffin–Siris32 (BRM) proliferative effects wild-types29 Nicolaides- Baraitser33,34

Abbreviations: BAF, BRG1-associated factors; ND, not determined.

hereditary cancer syndrome in which patients develop multiple observations, coupled with the lack of BRM (also called SMARCA2) non-vestibular schwannomas, and with the development of mutations in tumors of sporadic origin, might imply that BRM has multiple meningiomas.21,22 Regardless of whether the mutations no role in cancer. However, a complete loss of BRM expression has at SNF5 in the MRTs, schwannomas or meningiomas arise been reported in some tumors,4 which suggests that additional somatically or already exist in the germ line, the second allele is studies are required to rule out definitively the participation of also altered by loss of heterozygosity, which is consistent with the BRM in cancer development. two-hit recessive model of oncogenesis. Moreover, the genetic mouse models support the implication of SNF5 in cancer development.23 Homozygous knockout mice for Snf5 experience Germ-line mutations at SWI/SNF and autism-related disorders embryonic lethality and, similarly to what happens in humans, Recently, germ-line mutations at several of the components of the heterozygous mice are born and appear normal. However, at 5 SWI/SNF chromatin-remodeling complex have also been linked to weeks of age, these mice start developing tumors that look similar human syndromes across the spectrum of autism disorders. In to human MRTs, frequently developing metastases in the lungs particular, with the autosomal dominant syndromes Nicolaides– and lymph nodes.23 Baraitser and Coffin–Siris, which are very rare diseases (o100 On the other hand, the relationship of inactivating mutations at cases of each, worldwide) and show several common clinical BRG1 with human cancer predisposition is not well established. characteristics, including multiple congenital malformations, One publication has reported a BRG1 germ-line nonsense microcephaly and intellectual disability.30–34 Figure 2 summarizes mutation associated with the predisposition to developing the various mutations found in these syndromes and their MRTs,24 the same cancer syndrome as that associated with SNF5 location, distributed into the different domains of the proteins. It mutations. Consistent with the BRG1 cancer-related syndrome, is still unclear how germ-line mutations at these genes can give Brg1 þ / À mice have an increased risk of developing cancer rise to either a cancer predisposition syndrome or a developmen- (Table 1). However, in contrast to the MRT syndrome, Brg1 þ / À mice tally related syndrome, which are disorders of distinct nature. In are prone to developing epithelial tumors at different locations, this regard, it is worth mentioning that, in contrast to what such as the neck and the groin, which display different features of happens in cancer, the mutations in BRG1 and SNF5 in individuals epitheloid origin.25,26 Complementary to these data, lung Brg1- with the developmental syndromes were non-truncating (either targeted heterozygous mice also develop tumors in response to missense changes or in-frame deletions), implying that they exert carcinogens.27 Other tissue-specific models for gain-of-function or dominant-negative effects.32 Conversely, the Brg1 have been generated that trigger specific effects.28 Some of patterns of alterations at the ARID1A and ARID1B genes, typically these models are discussed below. mutations that predict truncated proteins, are very similar in the In contrast to Brg1 and Snf5, Brm knockout mice are viable and two types of disease. The reasons for this are not yet clear and do not have an increased risk of developing tumors.29 These merit intensive investigation. In spite of this, there are some

& 2014 Macmillan Publishers Limited Oncogene (2014) 2681 – 2689 The SWI/SNF genetic blockade OA Romero and M Sanchez-Cespedes 2684

Figure 2. Schematic representation of the protein members of the SWI/SNF complex mutated in the Coffin–Siris and Nicolaides–Baraitser syndromes. The type and location of the mutations are depicted, according to the main protein domains. SNF2, family N-terminal domain; QLQ, –leucine–glutamine domain; HSA, small helicase/SANT-associated domain; BRK, brahma and kismet domain; DEXDc; DEAD- like superfamily, ATP-binding; HELICc, Helicase superfamily c-terminal domain; DUF3518; domain of unknown function. ARID, AT-rich interactive domain 1A, DNA-binding domain. *Identical mutations were found in more than one individual. Underlined: identical mutations found in human cancer (COSMIC: http://cancer.sanger.ac.uk/cosmic/).

identical mutations that have been found both in cancer and in which are due to germ-line mutations at ATRX and SRCAP, the developmental syndromes (Figure 2). respectively.35,36 Despite all the uncertainties, it is worth mentioning that alterations in the brain are related features in these diseases. For example, the main clinical observations in individuals INVOLVEMENT OF THE SWI/SNF COMPLEX IN CELL with the Nicolaides–Baraitser and Coffin–Siris syndromes are DIFFERENTIATION microcephaly and severe intellectual disability. In this regard, a The SWI/SNF complex regulates transcription through its ability small percentage of the Brg1 þ / À and Smarcc1 þ / À mice are born to remodel chromatin. Despite having no intrinsic ability to with dire neurological abnormalities such as exencephaly, a bind DNA, the SWI/SNF complex is commonly recruited to gene condition where the brain is located outside of the skull, due promoters by transcription factors. Once there, the complex to an abnormal closure of the neural tube (Table 1). In addition, remodels the chromatin structure by the ATP-dependent disrup- among the types of cancer suffered by individuals that inherit an tion of DNA–histone interactions at the nucleosomes to activate/ SNF5 mutation are a variety of tumors of the central nervous repress .37 In this way, the complex acts as a system.21,22 Altogether, these observations highlight the transcriptional regulator of large sets of genes involved in multiple importance of an intact SWI/SNF complex for correct developmental pathways, including early embryonic development development and brain homeostasis. and tissue specification.37 Moreover, the SWI/SNF complex Finally, it is worth pointing out that, similar to what containing BRG1 has been shown to participate in the happens with the SWI/SNF complex, alterations at genes involved reprogramming of somatic cells.38 in other chromatin-remodeling complexes have also been The SWI/SNF complex is involved in the differentiation linked to developmentally related disorders, involving of a variety of mammalian tissues, for example, adipocytes, intellectual disability such as the alpha thalassemia/ erythropoietic cells, hematopoietic cells, hepatocytes, neurons, mental retardation X-linked and the Floating Harbor syndromes, osteoblasts and skeletal muscle, among others.25,39–44 BRG1 has

Oncogene (2014) 2681 – 2689 & 2014 Macmillan Publishers Limited The SWI/SNF genetic blockade OA Romero and M Sanchez-Cespedes 2685 been the best studied SWI/SNF component in this regard, and the normal lung gene expression signature.64 Conversely, it has been requirement of BRG1 for the appropriate differentiation of most shown that the loss of SNF5 increases the expression of the mammal tissues is well known.37 In this regard, the tissue-specific polycomb gene EZH2, triggering the activation of stem-associated knockout mice models for Brg1 provide with important programs.65 These observations indicate that abrogation of the information about the role of Brg1 in cell differentiation.28 For SWI/SNF complex activity enables the cancer cell to maintain example, a Brg1 deletion in the endocardium lead to embryonic undifferentiated gene expression programs. Overall, this is lethality due to impaired ventricular trabeculation during consistent with the role of the SWI/SNF complex in cell cardiogenesis.25 Similarly, brain-specific deletions of Brg1 cause differentiation and tissue specification. defects in neural stem/progenitor cell maintenance, impaired It is very likely that the maintenance of stem-associated gliogenesis and defects in brain development (exencephaly). programs of gene expression, acquired by the cancer cell through Furthermore, the conditional deletion of Brg1 in developing the inactivation of the SWI/SNF complex, is related to the impaired hematopoietic and endothelial cells leads to abnormalities in ability of the cell to respond to signaling. Retinoic erythropoiesis,44 and the Brg1 deletion in the thymus has as a acid (RA) is one of the essential compounds controlling embryonic consequence a dramatic reduction in total thymocyte cellularity development and tissue specification. It acts on progenitor cell and specially in CD4 þ CD8 À or CD4 À CD8 þ cells.43 populations to ensure the correct development of almost every The involvement of the SNF5 component in tissue differentia- embryonic tissue, including lung, pancreas, thyroid, parathyroid, tion is also well established and the abrogation of SNF5 expression thymus, specific cardiac population and several neural struc- by RNA interference is known to prevent neural differentiation in tures.66 Several observations have established a connection the presence of nerve growth factor.45 SNF5 is also essential for between a deficient response to RA and GCs with cancer. For hepatocyte and adipocyte differentiation.41,46 Furthermore, example, it is well known that many cancer cells have lost the BAF60c has been implicated in the differentiation of muscle/ capability of responding to nuclear receptor signaling, despite heart and retina,47–49 and in the insulin-induced lipogenic gene expressing nuclear receptors.67 Furthermore, RA deficiency activation in the liver,50 whereas BAF200 is essential for osteoblast promotes the generation of lung tumors in mice,68 whereas a differentiation.51 The participation of other components of failure to respond to GCs, is a risk factor for lung cancer, especially the SWI/SNF complex in tissue-specification processes is not well in smokers.69 Moreover, it has recently been demonstrated that understood. BRG1 inactivation in lung, breast and prostate cancer cells The role of the SWI/SNF complex in cell differentiation and conferred acquired refractoriness to RA and GC receptor tissue-specification relates to its dynamic DNA specificity and, signaling, whereas re-expression of BRG1 restored sensitivity.64 therefore, the ability to control specific gene expression programs, The involvement of BRG1 and the SWI/SNF complex in depending on the physiological environment of the cell. The mediating the action of the RA and GCs is also therapeutically control over the cell environment exerted by SWI/SNF is related to important. GCs have anti-inflammatory properties and are widely its critical regulation of nuclear receptor hormone-responsive used to treat inflammatory conditions and some types of cancer.69 promoters. Studies suggest that nuclear receptors recruit SWI/SNF For example, GCs are used in the curative treatment of acute activity to gene-specific promoters, in a ligand-dependent lymphoblastic leukemia. Resistance to GCs, which is an important manner, by which SWI/SNF functions to remodel the chromatin adverse prognostic factor in newly diagnosed acute lymphoblastic architecture. Components of the SWI/SNF complex bind to various leukemia patients, is associated with a lower level of expression of nuclear receptors, for example, , progesterone genes for core subunits of the SWI/SNF complex, that is, BRG1, receptor, , (GR), retinoic ARID1A and SNF5.70 RA is also used in cancer treatment, acid receptor (RAR), peroxisome proliferator-activated receptor specifically in some neuroblastomas and in acute promyelocytic gamma (PPARg) and vitamin D3 receptor, among others, leukemia. The latter is characterized by enduring the to change gene expression programs, accordingly.52–56 For promyelocytic leukemia–RARa gene fusion that has a critical role example, it is known that upon exposure to glucocorticoids in its genesis and that is the target of retinoid therapy.71 In (GCs), GR undergoes a structural conformational change that neuroblastoma cells, we demonstrated that the depletion of BRG1, drives translocation from the cytoplasm to the nucleus, where it with the use of small interference RNA, reverted the capability of binds the chromatin remodelers, including the SWI/SNF complex, the cells to respond to treatment with RA.64 Further, it is well to modify gene expression.57 Adipocyte differentiation requires established that breast and ovarian cancer are often resistant to the cooperation between various nuclear receptors, including GR, treatments with estrogen antagonists and that some prostate and PPARg, in addition to chromatin cancers are refractory to antiandrogen-based therapies. As remodeling.58 Cell metabolism is another process controlled inactivation at BRG1, SMARCC1 or ARID1A, among others, are by the interaction of nuclear receptor with the SWI/SNF present in breast, ovarian and prostate cancer (Table 1), it is complex. In this regard, the PPARg interacts with the SWI/SNF reasonable to hypothesize that the resistance to these hormone- complex,54 to regulate adipogenesis, lipid metabolism and based treatments is due to a malfunction of the SWI/SNF complex. glucose homeostasis, and the induction of the PPARg nuclear In support of this, it is known that the response to cancer cells of during adipogenesis requires SWI/SNF estrogen receptor, or androgen receptor enzymes.59,60 In spite of all this knowledge, our understanding requires an intact SWI/SNF complex.72–74 of the specific gene targets that are regulated by BRG1 and the Although the role of the SWI/SNF complex in controlling cell SWI/SNF complex in each physiological atmosphere is still limited. differentiation is well known, it may not be the only mechanism The use of chromatin immunoprecipitation combined with by which its inactivation contributes to carcinogenesis. In this transcriptome analysis has revealed some of the targets of regard, the SWI/SNF complex is involved in other cell processes SWI/SNF activity, although the information is still fragmentary such as in early embryonic development, in DNA repair, in cell and incomplete.61–63 migration and in cell cycle. Some of these proceses are related to important functional pathways that are considered to have important roles in the genesis and the development of cancer CHROMATIN-REMODELING BLOCKADE AND HORMONE in humans, including the Hedgehog-Gli, interferon-:signaling, the REFRACTORINESS IN CANCER CELLS: EFFECTS ON ROCK1-RHOA transduction pathway, retinoblastoma, among CANCER THERAPEUTICS others.5,75,76 The relationship of SWI/SNF with some of these We recently demonstrated that restoration of BRG1 activity in lung functions may be through direct physical interactions, such as RB, cancer cells leads, at least to some extent, to the restitution of the LKB1, GLI, bCATENIN, SMADs, BRCA1 and CFOS, among others,28

& 2014 Macmillan Publishers Limited Oncogene (2014) 2681 – 2689 The SWI/SNF genetic blockade OA Romero and M Sanchez-Cespedes 2686

Figure 3. BRG1 and MYC functional connection and cancer development. Normal cells efficiently regulate the activity of MYC according to the cell environment, whereas in cancer cells MYC is de-regulated by different mechanisms. Cancer cells carrying inactivation of BRG1 (or of other SWI/SNF components) are unable to control the activity of MYC and are completely refractory to RA or GC treatment. Cancer cells with MYC amplification have also an uncontrolled activity of MYC but are moderately responsive to GA and RA. RA, retinoic acid, GC, glucocorticoids, TF, . NR, nuclear receptors.

and through the transcriptional regulation, by the SWI/SNF inactivate the SWI/SNF complex. In spite of the functional complex, of proteins involved in these processes.61,63 equivalence for cancer development, carrying either MYC activation or SWI/SNF-complex inactivation probably implies some different capabilities for the cancer cell. For example, we THE BRG1 AND MYC FUNCTIONAL CONNECTION reported that while lung cancer cells carrying inactivation of BRG1 Cancer genes encoding proteins that have equivalent biological were completely refractory to RA or GC treatment, the cells with function for cancer growth tend not to be simultaneously altered MYC amplification indicated a moderate response, measured as in the same tumor specimen. This hypothesis is borne out by the ability to increase the expression of target genes.64 Further, a the examples of the cell-cycle components RB and CDKN2A, and partial reduction in cell growth was observed after RA treatment in of the receptor/signal transducer EGFR and KRAS, which are lung cancer cell lines carrying MYC amplification.79 Figure 3 among the best established genes behaving with a pattern illustrates these characteristics. of mutually exclusive mutations in lung cancer.12 Therefore, Finally, it is important to consider the potential use of this identifying the genetic relationships between cancer genes may knowledge in cancer therapeutics. Although the therapies based provide hints about the biological function of the encoded protein on RA or GC are not currently of use for treating most solid in cancer development. tumors, perhaps in combination with other drugs, they could be Using lung cancer cell lines, we searched for genes that were used to treat cancers carrying amplified MYC. However, our altered only in BRG1 wild-type tumors and found that amplifica- current understanding of SWI/SNF biology suggests that tumors tion at any MYC-family members was mutually exclusive to BRG1 with inactivation of BRG1, and possibly of other components of inactivation,9 suggesting a functional relationship between the the SWI/SNF complex, will be intrinsically resistant. On the other SWI/SNF complex and MYC. In agreement with this, a strong hand, as an oncogene, the MYC protein is potentially ‘druggable’ inverse correlation was found between the expression profiles of and, in this regard, different researchers are investing efforts into the lungs of mice expressing tissue-specific activated Myc and that developing compounds that inhibit the activity of MYC. Should of lung cancer cell lines after restoring BRG1 activity.64 Additional anti-MYC drugs become available, it will be important to select observations that support the functional connection are that BRG1 tumors that are likely to respond to treatment with them. is recruited to the E-boxes, the MYC consensus region in the DNA, Although MYC-amplified tumors are likely to be sensitive, it is and that the complex is required to mediate gene transactivation difficult to predict whether tumors with genetically inactivated of MYC target genes.64,77 Moreover, recruitment of SWI/SNF to components of the SWI/SNF complex will respond to these MYC-binding promoters is also dependent on the MYC-INI1 therapies. interaction.78 Overall, these observations strongly suggest that the tumor-suppressor role of BRG1 and of the SWI/SNF complex involve, among other factors, the control of MYC activity. Thus, for FUTURE PERSPECTIVES the cancer cell, enduring oncogenic activation at any of the MYC Gene alterations that abrogate the activity of several chromatin- family of genes is, to some extent, functionally tantamount to remodeling factors, especially those of the SWI/SNF complex, are

Oncogene (2014) 2681 – 2689 & 2014 Macmillan Publishers Limited The SWI/SNF genetic blockade OA Romero and M Sanchez-Cespedes 2687 emerging as widespread phenomena in cancer. In as much as an 19 Gayther SA, Batley SJ, Linger L, Bannister A, Thorpe K, Chin SF et al. Mutations abnormal chromatin-remodeling function is expected to be critical truncating the EP300 acetylase in human cancers. Nat Genet 2000; 24: 300–303. for cancer development, attempts to elucidate their biological 20 Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K et al. Driver repercussions are needed before our knowledge can influence mutations in histone H3.3 and chromatin remodelling genes in paediatric clinical management. Of special interest is the involvement of the glioblastoma. Nature 2012; 482: 226–231. 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