SNF chromatin remodeling enzymes in melanocyte differentiation and melanoma.

NIH Public Access Author Manuscript Crit Rev Eukaryot Gene Expr. Author manuscript; available in PMC 2014 July 21.

NIH-PA Author Manuscript

Published in final edited form as: Crit Rev Eukaryot Gene Expr. 2014 ; 24(2): 151–161.

SWI/SNF Chromatin Remodeling Enzymes in Melanocyte Differentiation and Melanoma A. Mehrotra, G. Mehta, S. Aras, A. Trivedi, and I.L. de la Serna* Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH

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 melanocytes. 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.

Keywords melanoma; microphthalmia-associated transcription factor; SOX10; SWI/SNF chromatin remodeling enzymes; gene expression

I. INTRODUCTION


Melanocytes are pigment-producing cells found in the basal layer of epidermis, hair follicles, the inner 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 epidermal melanocytes. Melanocytes comprise approximately 2% of the cell population of the skin. They synthesize melanin in specialized organelles called melanosomes and transfer the melanosomes to keratinocytes, 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 activation of melanocyte-specific genes, which have functions in melanin synthesis and melanosome biology, motility, and survival. Microphthalmia-associated transcription factor (MITF) is critically required for melanocyte specification, differentiation, and survival, 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

© 2014 Begell House, Inc. * 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; [email protected].

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melanocyte differentiation. 4 Interestingly, both SOX10 and MITF also have important roles in the oncogenic transformation of melanocytes to melanoma.5,6 How transcription factors that are intimately involved in differentiation, a process that often is associated with decreased proliferation, also contribute to oncogenic transformation is not well understood. An important consideration is the interaction of these transcription factors with chromatin remodeling enzymes to activate specific 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 conserved, multisubunit complexes of 1–2 MDa that utilize the energy derived from adenosine triphosphate (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 classified 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 vitro, 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 development. 14–20 Studies indicate that SWI/SNF enzymes are required for both embryonic stem cell pluripotency as well as cellular differentiation.21,22 SWI/SNF enzymes have been shown to interact with MITF and SOX10.23–25 In particular, the interaction between MITF and SWI/SNF enzymes has been demonstrated to be important for melanocyte differentiation and in melanoma.23,24 This review focuses on the studies implicating 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 epidermis, 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 related to Schwann cells, each requiring the activity of SOX10.28 It is MITF, however, that commits precursors to the melanocyte lineage and is considered the master regulator of melanocyte differentiation. 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 lineages, including Schwann cells and melanocytes.29 In melanocytes, SOX10 activates MITF expression and contributes to the expression of a subset of MITF target genes involved in melanin synthesis, such as tyrosinase, tyrosinase-related protein 1, and

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dopachrome tautomerase.30–33 SOX10 also is required for the differentiation of other neural crest lineages, including Schwann cells. SWI/SNF enzymes 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 complex interact with SOX10 during melanocyte differentiation or in melanoma.


MITF is a basic helix-loop-helix leucine zipper transcription factor that regulates gene expression by binding to canonical E box elements in the promoter region of its target genes either as homodimer or heterodimer with other related family 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 epithelial cells of the eye.38–40 In the melanocyte lineage, MITF promotes survival, proliferation, and differentiation 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 encoding 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 melanocyte 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 frequently progress to melanoma and to be required for melanoma proliferation and survival.6 MITF is considered a lineage addiction oncogene that promotes melanoma proliferation and survival.49 The MITF gene is amplified in approximately 10–20% of human melanomas and promotes oncogene-induced transformation of melanocytes and melanoma 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 differentiation as well as to increase survival of melanoma cells that were exposed to a chemotherapeutic agent or to UV radiation.24,47 One mechanism by which BRG1 promotes survival from UV radiation 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 Crit Rev Eukaryot Gene Expr. Author manuscript; available in PMC 2014 July 21.

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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 dysplastic nevi, 90 primary melanomas, and 47 metastatic melanomas, BRG1 expression was significantly higher in primary and metastatic melanoma compared to dysplastic nevi.59 A recent study reported heterogeneous staining of BRG1 in primary melanoma and occasional lack of detectable BRG1 expression in some tumors.36 Yet another study indicated that BRG1 messenger RNA levels were significantly higher in stage IV melanoma samples 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 function may be compromised in a small subset of melanomas. However, the concomitant loss of BRG1 and the alternative ATPase BRM has not been reported. 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 MITFdependent 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 significantly inhibits the expression of most MITF target genes, including the proproliferative and survival genes CDK2, TBX2, and BCL2, thus compromising tumorigenicity.24 However, BRM cannot compensate for BRG1 in the expression of all MITF target genes, indicating that BRM only partially compensates for BRG1 loss.47 Interestingly, disruption of BRM in mice does not result in an obvious 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 (Table 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 acetylated histones and potentially mediate other protein– protein interactions.66,67 BAF180 is thought to function as a targeting subunit for the PBAF complex to specific loci. Mice with BAF180 deletions have severe cardiac defects, with an impaired epithelial-to-mesenchymal transition, and die


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during 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 carcinomas and is thought to function as a tumor suppressor by interacting with the p53 protein to promote cell cycle arrest and senescence.72–74 Interestingly, BAF180 expression was found to be low in a subset of melanoma cell lines and dispensable for MLIAP 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 dependent 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 including 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 absence of BAF180 and is required for activation of a subset of interferon-α-inducible genes independent of BAF180. Thus, PBAF complexes containing or lacking BAF180 may regulate a distinct set of genes.


ARID2 mutations have been detected in hepatitis C virus–associated hepatocellular carcinomas,78 non-small-cell lung cancer,79 pancreatic cancer,80 and melanoma53,55–57 (Table 1). The studies of melanoma identified ARID2 as the SWI/SNF component 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 suppressor.


Two proteins containing an AT-rich DNA domain, ARID1A (BAF250A) and ARID1B (BAF250B), are highly homologous but mutually exclusive components of BAF complexes.10 Deletion of ARID1A in mice results in early embryonic lethality. ARID1A was found to be required for embryonic cell self-renewal as well as for differentiation into mesoderm-derived cardiomyocytes and adipocytes, but not for ectoderm-derived neurons. 20 Furthermore, deletion of the DNA-interacting domain of ARID1A in mice disrupts SWI/SNF binding to target sites and leads to embryonic lethality.81 Biallelic inactivation of ARID1B in embryonic stem cells results in reduced proliferation and self-renewal capacity.82 ARID1A and ARID1B have different expression patterns during embryonic development83 and opposing roles in cell cycle regulation during osteoblast differentiation. 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 hepatocellular 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 differentiation or in melanoma. BAF47 (SMARCB1) is a core component of SWI/SNF chromatin remodeling complexes that is required for optimum SWI/SNF chromatin remodeling activity in vitro.11 Deletion of the BAF47 gene results in early embryonic lethality.15–17 Interestingly, BAF47 heterozygous


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mice develop tumors with rhabdoid features that display loss of heterozygosity. 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 schwannomatosis. 92 In melanoma, one study indicates that downregulation of BAF47 expression occurs in a significant number of primary and metastatic melanomas and correlates with poor prognosis.52 Mutations of BAF47 also have been detected in melanoma cell lines (Table 1).55 Interestingly, BAF47 is required for oncogene-induced senescence of human melanocytes.93 BAF47 also has been shown to interact with MITF, suggesting that it may be required 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 expression 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 enzymes 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 concomitantly 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 survival 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 enzymes 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 mutagenesis and genomic instability resulting from defective DNA repair. A better understanding of this aspect of SWI/SNF function in melanocytes may help illuminate the role that these enzymes have in the initiation and progression of melanoma.

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


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ABBREVIATIONS NIH-PA Author Manuscript

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

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NIH-PA Author Manuscript NIH-PA Author Manuscript

FIG. 1.

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

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FIG. 2.

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

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TABLE 1


List of Mutations in SWI/SNF Components That Have Been Reported to Occur in Melanoma Gene

Aliases

Chromosome

Mutation

Reference

1/121 Nonsense

53

SMARCA4

BRG1

19

3/7 Nonsynonymous

54

1/14 Nonsynonymous

55

SMARCA2

BRM

9

1/7 Nonsynonymous

54

ARID1A

ARID1B


ARID2

SMARCB1

BAF250A, SMARCF1

BAF250B

BAF200

BAF47, INI1, SNF5

3/121 Nonsense

53

2/7 Nonsense

54

1/7 Nonsynonymous

54

1/8 Nonsynonymous

56

1/14 Nonsynonymous

55

3/121 Nonsense

53

1

6

12

22

3/121 Nonsense

53

6/121 Nonsense

53

2/121 Splice site

53

1/121 Frameshift

53

6/97 Nonsense

57

5/97 Frameshift

57

1/8 Nonsense

56

2/14 Nonsense

55

2/14 Nonsynonymous

55

NIH-PA Author Manuscript Crit Rev Eukaryot Gene Expr. Author manuscript; available in PMC 2014 July 21.

SNF chromatin remodeling complexes and cancer.

SNF chromatin remodeling complex regulates a non-chromatin substrate.

SNF chromatin-remodeling complexes in cardiovascular development and disease.

SNF Chromatin Remodeling Complex Controls Pluripotency and Endodermal Differentiation in Human ESCs.

SNF) Complexes in Neural Development and Disorders.

Chromatin dynamics: interplay between remodeling enzymes and histone modifications.

SNF complexes to chromatin remodeling in cancer.

EBP.

SNF chromatin remodeling complex, in breast cancer.

The melanocyte and melanoma.

SNF-Mediated Chromatin Remodeling.

SNF chromatin-remodeling complexes function in noncoding RNA-dependent assembly of nuclear bodies.

SNF chromatin remodeling complex.

SNF Chromatin-Remodeling Accessory Subunits During Caenorhabditis elegans Development.

SNF Controls Multidrug Resistance by Transcriptionally Regulating the Drug Efflux Pump ABCB1.

KAT5-mediated SOX4 acetylation orchestrates chromatin remodeling during myoblast differentiation.

Advances in melanocyte and melanoma biology.

Melanocyte and melanoma cell activation by calprotectin.

Chromatin-Remodelling Complex NURF Is Essential for Differentiation of Adult Melanocyte Stem Cells.

Ultraviolet involvement in melanocyte transformation to melanoma.

SNF chromatin remodeling enzyme ATPase, is required for maintenance of nuclear shape and integrity.

Snf chromatin remodeling complexes modulates Pdx1 activity in islet β cells.

SNF chromatin remodeling complex in maintaining the stemness of glioma initiating cells.

Replication-Coupled Nucleosome Assembly and Positioning by ATP-Dependent Chromatin-Remodeling Enzymes.