ZMYND8-regulation of MITF as potential therapeutic target in melanoma

黑色素瘤是一种高度侵袭性和日益常见的癌症，其特征是激活特定基因的突变，这些突变激活导致肿瘤进展的生存途径。虽然几种抑制剂已经成功进入临床测试，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治疗有反应，但几个月后不可避免地会复发。目前没有针对这些患者的治疗方法。尽管与一种名为MITF的蛋白质有关，MITF是黑色素瘤细胞表型的主要调节因子，但支撑MITF控制的确切机制仍然不清楚。尽管人们对MITF的衰减知之甚少，但它的水平与耐药性有关，低水平预示着一种名为BRAF的蛋白质的激活突变控制着重要的细胞功能。这项研究将探讨一种名为ZMYND8的蛋白质在影响或控制患者来源的耐药黑色素瘤细胞系中MITF水平的作用。我们发现ZMYND8作用于组装阻断蛋白质表达的因子，我们进一步发现其中一个因子与MITF的表达直接相关。因此，这个项目将探索黑色素瘤主调控因子是如何反过来被调控的，提供关于黑色素瘤耐药与敏感性的信息。我们预计，这项研究将为靶向其他耐药的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.