Abstract：
Identification of potential key targets of melanoma, a fatal skin malignancy, is critical to the development of new cancer therapies. Lysine methyltransferase 2A (KMT2A) promotes melanoma growth by activating the human telomerase reverse transcriptase (hTERT) signaling pathway; however, the exact mechanism remains elusive. This study aimed to reveal new molecular targets that regulate KMT2A expression and melanoma growth. Using biotin-streptavidin-agarose pull-down and proteomics, we identified Damage-specific DNA-binding protein 2 (DDB2) as a KMT2A promoter-binding protein in melanoma cells and validated its role as a regulator of KMT2A/hTERT signaling. DDB2 knockdown inhibited the expression of KMT2A and hTERT and inhibited the growth of melanoma cells in vitro. Conversely, overexpression of DDB2 activated the expression of KMT2A and promoted the growth of melanoma cells. Additionally, we demonstrated that DDB2 expression was higher in tumor tissues of patients with melanoma than in corresponding normal tissues and was positively correlated with KMT2A expression. Kaplan-Meier analysis showed a poor prognosis in patients with high levels of DDB2 and KMT2A. Overall, our data suggest that DDB2 promotes melanoma cell growth through the transcriptional regulation of KMT2A expression and predicts poor prognosis. Therefore, targeting DDB2 may regulate the effects of KMT2A on melanoma growth and progression, providing a new potential therapeutic strategy for melanoma.
摘要：
确定黑色素瘤的潜在关键靶标，致命的皮肤恶性肿瘤,对新的癌症疗法的发展至关重要。赖氨酸甲基转移酶2A（KMT2A）通过激活人端粒酶逆转录酶（hTERT）信号通路促进黑色素瘤生长；然而，确切的机制仍然难以捉摸。本研究旨在揭示调节KMT2A表达和黑色素瘤生长的新分子靶标。使用生物素-链霉亲和素-琼脂糖下拉和蛋白质组学，我们将损伤特异性DNA结合蛋白2(DDB2)鉴定为黑色素瘤细胞中的KMT2A启动子结合蛋白,并验证了其作为KMT2A/hTERT信号调节因子的作用.DDB2敲除抑制了KMT2A和hTERT的表达，并抑制了黑色素瘤细胞的生长。相反，DDB2的过表达激活了KMT2A的表达并促进了黑色素瘤细胞的生长。此外,我们证明DDB2在黑色素瘤患者的肿瘤组织中的表达高于相应的正常组织，并且与KMT2A的表达呈正相关。Kaplan-Meier分析显示DDB2和KMT2A水平高的患者预后不良。总的来说,我们的数据提示DDB2通过转录调控KMT2A表达促进黑色素瘤细胞生长,并预测预后不良.因此,靶向DDB2可能调节KMT2A对黑色素瘤生长和进展的影响，为黑色素瘤提供了一种新的潜在治疗策略。
