KMT2A与黑色素瘤发生发展密切相关，研究其表达调控机制意义重大。前期研究我们证明KMT2A在黑色素瘤中高表达、通过上调端粒酶逆转录酶（hTERT）促进黑色素瘤生长。进一步，我们垂钓发现DDB2是KMT2A的上游调控蛋白，其特异性结合KMT2A启动子，并激活其转录，进而促进hTERT表达和肿瘤细胞生长。据此，我们推测DDB2通过靶向上调KMT2A/hTERT通路调控黑色素瘤生长。本项目拟在黑色素瘤细胞和动物模型中稳定敲低或过表达DDB2，研究其对KMT2A表达、启动子活性、端粒酶活性、端粒稳定性、细胞干性、肿瘤生长等的调控，揭示DDB2调控KMT2A/hTERT通路和黑色素瘤生长的分子机制；并利用组织芯片和临床资料，分析黑色素瘤患者中三者的表达相关性，明确它们与黑色素瘤生长、分期、生存、预后等的关系及临床意义。本项目旨在确立DDB2/KMT2A/hTERT作为黑色素瘤治疗新靶点提供实验依据

KMT2A is closely related to tumorigenesis and development. It is of importance to investigate its expression regulation mechanism. In our preliminary study, we have shown that KMT2A is highly expressed in melanoma. It promotes tumor growth by upregulating hTERT. In addition, we have also pulled down and identified DDB2 as a KMT2A regulatory protein. DDB2 can bind to the KMT2A promoter and activates KMT2A transcription, thus promoting hTERT expression and tumor cell growth. Therefore, we propose that DDB2 regulates melanoma growth via targeting KMT2A/hTERT signaling pathway. In this study, we will knockdown or overexpress DDB2 in human melanoma cell lines and animal models, and then study the effects of DDB2 on KMT2A expression and promoter activity, telomerase activity, telomere stability, cell stemness and tumor growth, thereby revealing the mechanism of DDB2 in the regulation of KMT2A/hTERT pathway and melanoma growth. Moreover, we will use tissue array and clinical data to analyze the expression levels and the correlation of DDB2/KMT2A/hTERT in tumor tissues from melanoma patients, and to evaluate their relationship with melanoma growth, pathological staging，survival and prognosis, as well as the clinical implication. The results from this study will provide experimental basis for the identification of the DDB2/KMT2A/hTERT signaling as a new therapeutic target for melanoma treatment.