ZMYND8-regulation of MITF as potential therapeutic target in melanoma

黑色素瘤是一种高度侵袭性和越来越常见的癌症，其特征在于激活特定基因中的突变，这些基因激活负责生存的途径，导致肿瘤进展。尽管几种抑制剂已成功进入临床试验，效果显著，但携带上述突变的患者最初对高效黑色素瘤消退的治疗有反应，但几个月后不可避免地复发。目前还没有针对这些患者的治疗方法。尽管已经发现了一种称为MITF的蛋白质，它是黑色素瘤细胞表型的主要调节因子，但支持MITF控制的精确机制仍然难以捉摸。尽管事实上，MITF的衰减是知之甚少，其水平已与耐药性，与低水平预测耐药性携带激活突变的蛋白质称为BRAF，控制重要的细胞functions.This研究将检查一个名为ZMYND8的蛋白质在影响或控制MITF水平的作用，在患者衍生的耐药性黑色素瘤细胞系的患者。我们发现ZMYND 8可以组装阻止蛋白质表达的因子，我们进一步发现其中一个因子与MITF表达直接相关。因此，该项目将探索黑色素瘤主调节因子如何反过来调节，提供黑色素瘤抗性与敏感性的信息。我们预计这项研究将为靶向耐药黑色素瘤提供新的可能性。

Melanoma is a highly aggressive and increasingly common cancer, characterized by activating mutations in specific genes which act to activate pathways responsible for survival leading to tumor progression. Although several inhibitors have successfully entered clinical testing with remarkable effects, patients carrying the aforementioned mutations initially respond to treatment with highly effective melanoma regression, they inevitably relapse after some months. There is currently no treatment for these patients. Although a link to a protein called MITF, which acts as a master regulator of the melanoma cell phenotype has been made, the precise mechanisms underpinning MITF's control remains elusive. Despite the fact that attenuation of MITF is poorly understood, its levels have been linked to drug resistance, with low levels predicting resistance to treatment in patients carrying activating mutations in a protein called BRAF, controlling important cellular functions.This study will examine the role of a protein called ZMYND8 in affecting or controlling MITF levels in patient derived, drug resistant melanoma cell lines. We discovered that ZMYND8 acts to assemble factors that block the expression of proteins and we further found one of these factors to be directly associated with MITF expression. This project will therefore explore how the melanoma master regulator is in turn regulated, providing information on resistance versus sensitivity in melanomas. We anticipate that this research will offer new possibilities in targeting otherwise drug resistant melanomas.