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Pro-Survival Role of MITF in Melanoma Mariusz L

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Pro-Survival Role of MITF in Melanoma Mariusz L View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector REVIEW Pro-Survival Role of MITF in Melanoma Mariusz L. Hartman1 and Malgorzata Czyz1 Melanoma is a therapy-resistant skin cancer due to apoptotic effectors, a wide range of transcription factors numerous mechanisms supporting cell survival. contributes to the melanoma pro-survival phenotype. Several Although components of melanoma cytoprotective of these transcription factors are constitutively active in a mechanisms are overexpressed in many types of number of tumors. Accordingly, the functional liaison tumors, some of their regulators are characteristic for between signal transducer and activator of transcription 3 melanoma. Several genes mediating pro-survival func- and NF-kB has been observed in many types of tumors tions have been identified as direct targets of micro- including melanoma, and this association results in the phthalmia-associated transcription factor (MITF), a increased expression of anti-apoptotic proteins (Lee et al., melanocyte-specific modulator also recognized as a 2009; Hartman and Czyz, 2013). lineage addiction oncogene in melanoma. BRAFV600E In contrast to signal transducer and activator of transcription 3orNF-kB, microphthalmia-associated transcription factor and other proteins deregulated in melanoma influence (MITF) is a transcription factor unique for melanocyte and MITF expression and activity, or they are the partners melanoma development. It is termed a lineage-addiction of MITF in melanoma response to radiotherapy and oncogene (Garraway et al., 2005); however, it is also chemotherapeutics. In this review, the pro-survival recognized as a suppressor of melanoma invasion and activity of MITF is discussed. metastasis (Pinner et al., 2009; Levy et al., 2010; Shah et al., Journal of Investigative Dermatology (2015) 135, 352–358; 2010; Thurber et al., 2011; Cheli et al., 2012; Bell et al., doi:10.1038/jid.2014.319; published online 21 August 2014 2014). MITF expression varies between melanoma specimens (Flaherty et al., 2012), and diverse mechanisms contribute to this phenomenon. Genomic amplification of MITF was INTRODUCTION initially found in 15–20% of melanomas (Garraway et al., Several biological capabilities are acquired during tumor 2005); however, targeted-capture deep sequencing has shown development, and many of them are integral components of no alteration in MITF copy number in 49 patient-derived most tumors (Hanahan and Weinberg, 2011). DNA damage melanoma metastases (Harbst et al., 2014). Diverse somatic caused by hyperproliferation and regulatory imbalances mutations have been found in MITF (Cronin et al., 2009). A resulting from elevated levels of oncogene signaling is SUMOylation-deficient E318K-mutated MITF has been compensated by the increased survival capacity of cancer identified as a variant present in patients with familial cells. Mechanisms responsible for the enhanced DNA repair melanoma (Bertolotto et al., 2011; Yokoyama et al., 2011). (Curtin, 2012) and resistance to multiple apoptotic signals Patients carrying this germline substitution, known as a (Hellwig et al., 2011) are common for diverse tumors. The medium-penetrance melanoma gene, suffer from multiple repertoire of other strategies to limit or circumvent cell death primary melanomas (Sturm et al., 2014). Melanoma-specific largely depends on the type of cells from which the tumor BRAFV600E substantially participates in control of MITF arises. expression and activity by maintaining a fine balance of Melanoma derives from pigment-producing melanocytes. opposing mechanisms (Levy et al., 2006; Goodall et al., These cells are characterized by pro-survival mechanisms that 2008; Pinner et al., 2009; Johanessen et al., 2013) (Figure 1). counteract damage-causing factors, including UV radiation As recently reviewed by Hartsough et al. (2014), the response and highly reactive intermediates of melanogenesis (Chen to RAF inhibitors, e.g., vemurafenib and dabrafenib, is et al., 2014; Denat et al., 2014). These complex mechanisms of resisting cell death, already active in melanocytes, are heterogeneous in melanoma, and the resistance further extended in melanoma cells. Upstream of anti- mechanisms developed during treatment might affect MITF activity as well. MITF expression might be also affected by mutations in its transcriptional regulators, e.g., SOX10 1Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz, Poland (Cronin et al., 2009) and ETV1 (Jane-Valbuena et al., 2010), Correspondence: Malgorzata Czyz, Department of Molecular Biology of or by alterations in the composition of microRNAs negatively Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, Lodz 92-215, regulating MITF transcript (Bemis et al., 2008; Segura et al., Poland. E-mail: [email protected] 2009; Haflidado´ttir et al., 2010; Luo et al., 2013). Abbreviations: BCL2, B-cell leukemia/lymphoma 2; BCL2A1, BCL2-related To link the level of MITF with the phenotype of melanoma protein A1; HGF, hepatocyte growth factor; HIF1a, hypoxia-inducible factor cells, a ‘‘rheostat’’ or ‘‘dynamic epigenetic’’ model was 1a; MITF, microphthalmia-associated transcription factor; ML-IAP, melanoma inhibitor of apoptosis created (Carreira et al., 2006). This model was profoundly Received 12 May 2014; revised 16 July 2014; accepted 18 July 2014; discussed and extended (Quintana et al., 2010; Bell and Levy, published online 21 August 2014 2011; Giuliano et al., 2011; Eccles et al., 2013; Bell et al., 352 Journal of Investigative Dermatology (2015), Volume 135 & 2015 The Society for Investigative Dermatology ML Hartman and M Czyz MITF in Melanoma Survival Gene Protein as a double-negative feedback loop, where MITF and MITF- expression level Activity dependent microRNAs can activate one state while BRAFV600E suppressing another (Bell et al., 2014), activated by PAX3- Ub BRN2 (Boyle et al., 2011; Eccles et al., 2013). Thus, cellular KIT CREB MITF context and tumor microenvironment are key factors influencing MITF expression and activity, and, as a result, cAMP USP13 LEF1 p21 the phenotype of melanoma cells can be dynamically β-cat modulated (Hoek and Goding, 2010; Quintana et al., 2010; Bell and Levy, 2011; Bell et al., 2014). In line with this, we ZEB2 V600E BRAF have shown recently that even small changes in the TYRO3 SOX10 P composition of the growth medium can significantly alter ATF2 P the MITF level and the phenotype of melanoma cells MITF p38 MITF P (Hartman et al., 2014). TGFβ GLI2 Although expression of several genes is regulated by MITF β V600E GSK3 in melanocytes and malignant melanoma cells, this review is BRAF BRN2 miR-101 PIAS3 miR-137 focused on MITF-dependent expression of proteins promoting SUMO PAX3 melanoma cell survival. HOXA1 miR-148 miR-182 Cofactors HIF1α DEC1 p300/CBP PRO-SURVIVAL ROLE OF MITF IN MELANOMA BRG1 (SWI/SNF) Almost 100 genes encoding proteins with diverse biological β-Catenin functions were identified as direct targets of MITF in mela- Figure 1. Overview of major mechanisms regulating MITF expression, its noma (Hoek et al., 2008; Widmer et al., 2012). MITF is a protein level, and activity in melanoma. A number of transcription factors critical transcription factor for the development of the promote MITF expression (shown in green) or inhibit its transcription (shown in melanocytic lineage (Opdecamp et al., 1997; Levy et al., red) via diverse signaling pathways. Recently identified regulators such as 2006) and regulates genes associated with melanogenesis and HOXA1 (Wardwell-Ozgo et al., 2014) and ZEB2 (Denecker et al., 2014) are cell differentiation, proliferation, and survival (Vachtenheim included. MITF transcript can be targeted by several microRNAs (Bemis et al., et al., 2010; Haq and Fisher, 2011; Koludrovic and Davidson, 2008; Segura et al., 2009; Haflidado´ttir et al., 2010; Luo et al., 2013). Phosphorylation and SUMOylation of MITF enhance its transcriptional activity 2013). Although pigment synthesis regulated by MITF is an (Levy et al., 2006; Yokoyama et al., 2011). BRAFV600E contributes to positive important mechanism protecting the skin against UV and negative regulation of MITF. MITF can be also subjected to USP13- radiation–induced damage (Choi et al., 2010; Haq and mediated deubiquitylation preventing its proteasomal degradation (Zhao et al., Fisher, 2011), MITF promotes melanocyte and melanoma 2011). HIF1a, hypoxia-inducible factor 1a; LEF1, lymphoid enhancer-binding cell survival also independently of melanin synthesis. factor 1; MITF, microphthalmia-associated transcription factor; TGFb, Several genes encoding anti-apoptotic proteins are direct transforming growth factor-b. MITF targets (Figure 2). A microarray-based study identified BCL2 (B-cell leukemia/lymphoma 2) as an MITF target gene in 2014). Depending on the expression level and posttrans- melanocytes (McGill et al., 2002). A functional E-box sequence lational modifications of MITF, melanoma cells can either at À 220 position was found in the BCL2 promoter, and differentiate or proliferate. High activity of MITF promotes nearest-neighbor analysis confirmed a tight correlation differentiation preceded by p16- and p21-mediated G1 cell between the expression of MITF and BCL2 in a panel of cycle arrest. Low MITF activity is attributed to the stem cell– primary human melanomas (McGill et al., 2002). BCL2 expres- like and invasive phenotype. Finally, prolonged MITF deple- sion, however, is relatively low in most melanomas compared
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