Critical ReviewsTM in Eukaryotic Gene Expression, 24(2):151-161 (2014)

1511045-4403/14/$35.00 © 2014 Begell House, Inc. www.begellhouse.com

SWI/SNF Chromatin Remodeling Enzymes in Melanocyte Differentiation and MelanomaA. Mehrotra, G. Mehta, S. Aras, A. Trivedi, & I.L. de la Serna*

Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH

* Address all correspondence to: I.L. de la Serna, Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine

and Life Sciences, 3035 Arlington Ave, Toledo, OH 43614; Tel.: (419) 383-4111; Fax: (419) 383-6228; ivana.delaserna@utoledo.edu.

ABSTRACT: Epidermal melanocytes are pigment-producing cells derived from the neural crest that protects skin from the damaging effects of solar radiation. Malignant melanoma, a highly aggressive cancer, arises from melano-cytes. SWI/SNF enzymes are multiprotein complexes that remodel chromatin structure and have extensive roles in cellular differentiation. Components of the complex have been found to be mutated or lost in several human cancers. This review focuses on studies that implicate SWI/SNF enzymes in melanocyte differentiation and in melanoma.

KEY WORDS: melanoma, microphthalmia-associated transcription factor, SOX10, SWI/SNF chromatin remodeling enzymes, gene expression

ABBREVIATIONS: ATP, adenosine triphosphate; BAF, BRG1/BRM-associated factor; MITF, microphthalmia-associated transcription factor; BAF, ML-IAP, melanoma inhibitor of apoptosis; PBAF, polybromo-associated factor; UV, ultraviolet.

I. INTRODUCTION

Melanocytes are pigment-producing cells found in the basal layer of epidermis, hair follicles, the in-ner ear, eye choroid, and heart.1 Making melanin to protect skin from the damaging effects of ultraviolet (UV) radiation from the sun is a key function of epi-dermal melanocytes. Melanocytes comprise approx-imately 2% of the cell population of the skin. They synthesize melanin in specialized organelles called melanosomes and transfer the melanosomes to ke-ratinocytes, the predominant epidermal component. Exposure to UV radiation leads to DNA damage in melanocytes and surrounding cells of the skin and is the single most critical environmental agent that promotes the development of melanoma.2

During melanocyte differentiation, a number of key transcription factors contribute to the activa-tion of melanocyte-specific genes, which have func-tions in melanin synthesis and melanosome biology, motility, and survival. Microphthalmia-associated

transcription factor (MITF) is critically required for melanocyte specification, differentiation, and sur-vival, as demonstrated by a loss of melanocytes in mice in which the expression of MITF is disrupted.3 Other transcriptional regulators including SOX10 also have crucial roles in melanocyte differentia-tion.4 Interestingly, both SOX10 and MITF also have important roles in the oncogenic transformation of melanocytes to melanoma.5,6 How transcription fac-tors that are intimately involved in differentiation, a process that often is associated with decreased pro-liferation, also contribute to oncogenic transforma-tion is not well understood. An important consider-ation is the interaction of these transcription factors with chromatin remodeling enzymes to activate spe-cific genes involved in melanocyte differentiation and melanoma. SWI/SNF chromatin remodeling enzymes have been shown to be important for the regulation of genes during cellular differentiation and in cancer.7,8

SWI/SNF enzymes are evolutionarily con-

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served, multisubunit complexes of 1–2 MDa that utilize the energy derived from adenosine triphos-phate (ATP) hydrolysis to alter chromatin structure and regulate gene expression.7 Diverse SWI/SNF complexes contain a catalytic subunit—BRG1 or BRM—and 8–12 accessory proteins (BRG1/BRM-associated factors [BAFs]). Furthermore, complexes containing BRG1 can be further clas-sified into polybromo-associated factor (PBAF) complexes, which uniquely contain BAF200 and BAF180,9 or BAF complexes, which uniquely contain BAF250A or BAF250B10 (Fig. 1). In vi-tro, chromatin remodeling is achieved by a core complex containing BRG1 or BRM, BAF47, BAF170, and BAF155.11 In vivo, additional BAFs are required for interactions with transcriptional activators and repressors.12,13 The BRG1 subunit and other SWI/SNF subunits, including BAF47, BAF60C, BAF155, BAF180, and BAF250A, have been shown to be essential for murine develop-ment.14–20 Studies indicate that SWI/SNF enzymes are required for both embryonic stem cell pluripo-tency as well as cellular differentiation.21,22

SWI/SNF enzymes have been shown to in-teract with MITF and SOX10.23–25 In particular, the interaction between MITF and SWI/SNF en-zymes has been demonstrated to be important for melanocyte differentiation and in melanoma.23,24 This review focuses on the studies implicat-ing SWI/SNF enzymes in the transcriptional regulation of melanocyte differentiation and in melanoma and discusses evidence indicating that components of the SWI/SNF complex are disrupted in melanoma.

II. MELANOCYTE DIFFERENTIATION

Melanocytes are derived from multipotent neural crest cells that migrate from the embryonic neural tube in a dorsolateral path to populate the epider-mis, hair follicles, and other regions.26 In contrast, neural crest cells that migrate ventrally give rise to neurons and Schwann cells. Some melanocytes also arise from Schwann cell precursors located in peripheral nerves.27 Melanoblasts, cells committed to the melanocyte lineage, are developmentally re-

lated to Schwann cells, each requiring the activ-ity of SOX10.28 It is MITF, however, that commits precursors to the melanocyte lineage and is con-sidered the master regulator of melanocyte differ-entiation.

SOX10 is a Sry-related high-mobility group box transcriptional regulator that is required for neural crest pluripotency and survival as well as for the differentiation of several neural crest lin-eages, including Schwann cells and melanocytes.29 In melanocytes, SOX10 activates MITF expres-sion and contributes to the expression of a subset

A.

B.

C.

Figure 1

ARID2

BAF180

BAF60ABRG1

BAF170BAF57

BAF53A

Baf47

β-ac�n

BAF53B

BAF60B

BAF60C

BAF155

BAF60ABRG1

BAF170

BAF57

ARID1A

BAF155

BAF53A

Baf47

β-ac�n

ARID1B

BAF53B

BAF60B

BAF60C

β-ac�n

BAF60ABRM

BAF170BAF57

ARID1A

BAF53ABaf47

BAF60B

BAF60C

ARID1B

BAF53B

BAF155

FIG.1: Heterogeneous SWI/SNF complexes contain-ing either BRG1 or BRM and associated factors exist in mammalian cells: PBAF (a), BAF(BRG1) (b), and BAF(BRM) (c).

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of MITF target genes involved in melanin synthe-sis, such as tyrosinase, tyrosinase-related protein 1, and dopachrome tautomerase.30–33 SOX10 also is required for the differentiation of other neural crest lineages, including Schwann cells. SWI/SNF en-zymes are required for SOX10 expression and for expression of SOX10 target genes during Schwann cell differentiation25,34,35 (Fig. 2). Interestingly, downregulation of the BRG1 subunit of SWI/SNF enzymes in melanoma cells compromises SOX10 expression.36 However, it is not known whether BRG1 or other components of the SWI/SNF com-plex interact with SOX10 during melanocyte dif-ferentiation or in melanoma.

MITF is a basic helix-loop-helix leucine zip-per transcription factor that regulates gene expres-sion by binding to canonical E box elements in the promoter region of its target genes either as homodimer or heterodimer with other related fam-ily members (TFE3, TFEB, and TFEC proteins).3,37 MITF plays a prominent role in the development of several different cell types, including melanocytes, osteoclasts, mast cells, and retinal pigment epithe-lial cells of the eye.38–40 In the melanocyte lineage, MITF promotes survival, proliferation, and dif-ferentiation of melanoblasts into melanocytes.3 It activates genes required for melanin synthesis and melanocyte function, including tyrosinase, TRP1, DCT,3 as well as genes required for survival and cell cycle regulation, including the genes encod-ing anti-apoptotic factors, BCL2 and melanoma inhibitor of apoptosis (ML-IAP), and cell cycle regulators (CDK2, p16INK4A, and p21WAF1/CIP1).41–45 SWI/SNF enzymes have been shown to

be required for MITF-mediated activation of me-lanocyte specific genes as well as the expression of MITF and the activation of MITF target genes that regulate proliferation and survival23,24,46,47 (Fig. 2). Furthermore, SWI/SNF enzymes interact with MITF in osteoclasts to activate osteoclast-specific genes.48

III. MELANOMA

Melanoma is an extremely aggressive malignancy with a tendency for widespread metastasis. The aggressive nature of melanoma is thought to be attributed at least in part to the activity of lineage-specific transcription factors such as SOX10 and MITF. SOX10 has been demonstrated to promote the formation of giant congenital nevi that fre-quently progress to melanoma and to be required for melanoma proliferation and survival.6 MITF is considered a lineage addiction oncogene that pro-motes melanoma proliferation and survival.49 The MITF gene is amplified in approximately 10–20% of human melanomas and promotes oncogene-in-duced transformation of melanocytes and melano-ma chemoresistance.50 There is evidence that SWI/SNF enzymes cooperate with MITF to promote melanoma tumorigenicity,24 as well as evidence that some SWI/SNF subunits are downregulated or mutated in melanoma.51–57

A. The SWI/SNF ATPases in Melanoma

BRG1 has been shown to promote melanoma dif-ferentiation as well as to increase survival of mela-

Figure 2

S O X 10

M IT FSWI/SNF

S chw ann cell specific genes

M elanocyte cell specific genesSWI/SNF

SWI/SNFSWI/SNF

FIG. 2: SWI/SNF interacts with SOX10 and MITF to activate melanocyte- and Schwann cell–specific genes.

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noma cells that were exposed to a chemotherapeu-tic agent or to UV radiation.24,47 One mechanism by which BRG1 promotes survival from UV radia-tion is by activating the MITF target gene, ML-IAP (BIRC7, livin). ML-IAP is a potent inhibitor of apoptosis that is highly expressed in melanoma and promotes aggressive behavior and poor response to chemotherapeutic agents.58 BRG1 was found to remodel chromatin on the ML-IAP promoter and to facilitate MITF and coactivator binding. Thus, BRG1 may promote melanoma survival after DNA damage, in part through interactions with MITF to activate the expression of this potent antiapoptotic gene. Interestingly, the requirement for BRG1 is not compensated by the alternative subunit BRM in several melanoma cell lines.47

There have been several reports of the status of BRG1 in melanoma. One study assayed BRG1 expression in 38 primary and metastatic melanoma samples by immunohistochemistry and found that BRG1 was lost in a significant number of these samples.51 In a larger study that compared 48 dys-plastic nevi, 90 primary melanomas, and 47 meta-static melanomas, BRG1 expression was signifi-cantly higher in primary and metastatic melanoma compared to dysplastic nevi.59 A recent study re-ported heterogeneous staining of BRG1 in primary melanoma and occasional lack of detectable BRG1 expression in some tumors.36 Yet another study in-dicated that BRG1 messenger RNA levels were significantly higher in stage IV melanoma sam-ples compared to normal and stage III melanoma samples.60 Interestingly, recent exome sequencing studies have detected BRG1 mutations at a low frequency in patient-derived melanoma samples53 (Table 1). These studies suggest that BRG1 func-tion may be compromised in a small subset of mel-anomas. However, the concomitant loss of BRG1 and the alternative ATPase BRM has not been re-ported. The expression of either BRG1 or BRM is downregulated in a subset of melanoma cell lines, and knocking down both ATPases in melanoma decreases proliferation and survival, suggesting that either the BRG1 or BRM subunit is required for melanoma tumorigenticity.24,46 The requirement for SWI/SNF activity is associated with MITF-de-

pendent and -independent functions.24,36,46,47,60

SWI/SNF complexes containing BRM have chromatin remodeling activities similar to those of complexes containing BRG1 in vitro, but several studies suggest that they have distinct functional roles in vivo.61 In one study, BRG1 was found to promote osteoblast differentiation, whereas BRM was found to maintain the proliferating precursor state.62 Disruption of BRM in mice does not affect embryonic development, whereas disruption of BRG1 is embryonically lethal.14,63 Downregulation of BRM in BRG1-deficient melanoma cells signif-icantly inhibits the expression of most MITF target genes, including the proproliferative and survival genes CDK2, TBX2, and BCL2, thus compromis-ing tumorigenicity.24 However, BRM cannot com-pensate for BRG1 in the expression of all MITF target genes, indicating that BRM only partially compensates for BRG1 loss.47 Interestingly, dis-ruption of BRM in mice does not result in an obvi-ous pigmentary phenotype,63 but exacerbates skin photocarcinogenesis.64 A hotspot mutation in BRM has been reported in nonmelanoma skin cancers.65 In a survey of 7 melanoma cell lines, one cell line was determined to have a mutation in BRM54 (Ta-ble 1). However, BRM expression was found to be infrequently downregulated in patient-derived melanoma samples.36,51

B. BAFs in Melanoma

BAF180 (polybromo or PBRM1) is an SWI/SNF subunit that is specific to the PBAF complex. It contains 6 bromodomains that interact with acety-lated histones and potentially mediate other pro-tein–protein interactions.66,67 BAF180 is thought to function as a targeting subunit for the PBAF complex to specific loci. Mice with BAF180 dele-tions have severe cardiac defects, with an impaired epithelial-to-mesenchymal transition, and die dur-ing embryogenesis.68,69 There is a requirement for BAF180 in gene activation by nuclear hormone receptors70 and for replication of damaged DNA.71 BAF180 is mutated in breast and renal cell carcino-mas and is thought to function as a tumor suppres-sor by interacting with the p53 protein to promote

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cell cycle arrest and senescence.72–74 Interestingly, BAF180 expression was found to be low in a sub-set of melanoma cell lines and dispensable for ML-IAP activation by BRG1.47 There have not yet been any reports of BAF180 mutations in melanoma. It is important to note that BAF180 stability is de-pendent on ARID2 (BAF200), another component of the PBAF complex.9

ARID2 (BAF200) is a subunit of the PBAF complex that contains a conserved N-terminal AT-rich DNA interaction domain and 2 conserved C-terminal acetylene zinc-finger motifs.75 Proteins containing ARID have been shown to be involved in a variety of domains biological processes in-cluding embryonic development.76 One report indicates that ARID2 is required for osteoblast differentiation.77 Interestingly, ARID2 can form a complex with other SWI/SNF subunits in the ab-sence of BAF180 and is required for activation of a subset of interferon-α-inducible genes indepen-

dent of BAF180. Thus, PBAF complexes contain-ing or lacking BAF180 may regulate a distinct set of genes.

ARID2 mutations have been detected in hepati-tis C virus–associated hepatocellular carcinomas,78 non-small-cell lung cancer,79 pancreatic cancer,80 and melanoma53,55–57 (Table 1). The studies of mel-anoma identified ARID2 as the SWI/SNF compo-nent that is most frequently mutated. In 2 of these studies, ARID2 mutations occurred at a significant frequency to be designated as driver mutations.53,57 There has not yet been any investigation into the biological function of ARID2 in melanocytes nor studies of how ARID2 might act as a tumor sup-pressor.

Two proteins containing an AT-rich DNA domain, ARID1A (BAF250A) and ARID1B (BAF250B), are highly homologous but mutually exclusive components of BAF complexes.10 Dele-tion of ARID1A in mice results in early embryonic

TABLE 1: List of Mutations in SWI/SNF Components That Have Been Reported to Occur in MelanomaGene Aliases Chromosome Mutation Reference

SMARCA4 BRG1 191/121 Nonsense3/7 Nonsynonymous 1/14 Nonsynonymous

535455

SMARCA2 BRM 9 1/7 Nonsynonymous 54

ARID1A BAF250A,SMARCF1 1

3/121 Nonsense2/7 Nonsense1/7 Nonsynonymous1/8 Nonsynonymous1/14 Nonsynonymous3/121 Nonsense

535454565553

ARID1B BAF250B 6 3/121 Nonsense 53

ARID2 BAF200 12

6/121 Nonsense2/121 Splice site1/121 Frameshift6/97 Nonsense5/97 Frameshift1/8 Nonsense2/14 Nonsense

53535357575655

SMARCB1 BAF47, INI1, SNF5 22 2/14 Nonsynonymous 55

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lethality. ARID1A was found to be required for embryonic cell self-renewal as well as for differ-entiation into mesoderm-derived cardiomyocytes and adipocytes, but not for ectoderm-derived neu-rons.20 Furthermore, deletion of the DNA-inter-acting domain of ARID1A in mice disrupts SWI/SNF binding to target sites and leads to embry-onic lethality.81 Biallelic inactivation of ARID1B in embryonic stem cells results in reduced prolif-eration and self-renewal capacity.82 ARID1A and ARID1B have different expression patterns during embryonic development83 and opposing roles in cell cycle regulation during osteoblast differen-tiation.84 Interestingly, ARID1A mutations have been reported in uterine and ovarian cancers,85,86 whereas ARID1B was found to be mutated at high frequency in breast cancer.87 Both ARID1A and ARID1B mutations have been reported in hepato-cellular carcinoma88,89 and neuroblastoma90 as well as in melanoma, although at a low frequency53–56 (Table1). ARID1A and ARID1B were both highly expressed in 2 surveys of melanoma cell lines.24,46 There have not yet been any functional studies of ARID1A and ARID1B in melanocyte differentia-tion or in melanoma.

BAF47 (SMARCB1) is a core component of SWI/SNF chromatin remodeling complexes that is required for optimum SWI/SNF chromatin remod-eling activity in vitro.11 Deletion of the BAF47 gene results in early embryonic lethality.15–17 Interesting-ly, BAF47 heterozygous mice develop tumors with rhabdoid features that display loss of heterozygos-ity. Thus, BAF47 acts as a classic tumor suppressor. Human malignant rhabdoid tumors frequently have inactivating mutations in the BAF47 gene,91 and mutations in BAF47 have been detected in schwan-nomatosis.92 In melanoma, one study indicates that downregulation of BAF47 expression occurs in a significant number of primary and metastatic mela-nomas and correlates with poor prognosis.52 Muta-tions of BAF47 also have been detected in mela-noma cell lines (Table 1).55 Interestingly, BAF47 is required for oncogene-induced senescence of hu-man melanocytes.93 BAF47 also has been shown to interact with MITF, suggesting that it may be re-quired for melanocyte differentiation.24

IV. CONCLUSIONS AND FUTURE DIRECTIONS

Current studies suggest that SWI/SNF complexes have a key role in the regulation of gene expres-sion during melanocyte differentiation and in melanoma. SWI/SNF enzymes have been shown to be required for the expression of 2 transcription factors, SOX10 and MITF, that promote melanoma tumorigenesis, as well as for activation of MITF target genes.24,36,46,47 Furthermore, SWI/SNF en-zymes are required for melanoma proliferation and can contribute to chemoresistance.24,36,46,47 These observations conflict somewhat with evidence indicating loss of function mutations in a subset of SWI/SNF genes or loss of expression of SWI/SNF components.51–57 However, it seems that the ATPases BRG1 and BRM are rarely concomi-tantly disrupted, suggesting that SWI/SNF activity may be compromised but not completely ablated in melanoma. Rather than a decrease in SWI/SNF activity, the disruption of BAFs such as ARID2 would be predicted to alter SWI/SNF interactions with transcription factors and affect recruitment of the complex to specific locations. Elucidation of the role of SWI/SNF-associated subunits in the transcriptional regulation of proliferation and sur-vival genes will increase our understanding of how disruption of SWI/SNF components alters gene expression in melanoma and provide insight into how some SWI/SNF components can act as tumor suppressors in this malignancy.

In addition to their function in transcriptional regulation, SWI/SNF chromatin remodeling en-zymes have recently been implicated in DNA damage signaling and repair pathways. It was demonstrated that BRG1 is recruited to sites of UV-induced damage, promotes chromatin relaxation, and facilitates nucleotide excision repair.94,95 BAF47 was shown to promote recruitment of the nucleotide excision repair machinery and checkpoint factors to UV-induced lesions.96 Thus, the loss of some SWI/SNF components in UV-exposed melanocytes may drive melanomagenesis because of increased muta-genesis and genomic instability resulting from de-fective DNA repair. A better understanding of this

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aspect of SWI/SNF function in melanocytes may help illuminate the role that these enzymes have in the initiation and progression of melanoma.

ACKNOWLEDGEMENTS

ILD was supported by grant no. R01(ARO59379) from the National Institute of Arthritis and Muscu-loskeletal and Skin Diseases.

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