SMDY3 是一种组蛋白赖氨酸 N-甲基转移酶，参与多种致癌过程，并被认为在多种癌症特征中发挥重要作用。最近，我们利用稀有三肽文库确定了 ATM、BRCA2、CHK2、MTOR、BLM、MET、AMPK 和 p130 为直接 SMYD3 相互作用因子，我们首先测试了它们与 SMYD3 的体外结合亲和力，然后将其用作计算机探针系统地搜索人类蛋白质组。在这里，我们使用这种创新方法进一步鉴定了参与关键癌症途径的 SMYD3 相互作用蛋白，并发现染色质重塑因子 EP300 和 TRRAP 直接与 SMYD3 相互作用，从而将 SMYD3 与新兴的“非突变表观遗传重编程”癌症标志联系起来。值得注意的是，我们在胃肠道癌细胞系（包括 HCT-116 细胞）中验证了这些相互作用，这些细胞在 EP300 中存在 C 端截短突变，表明 EP300 通过其 N 端区域与 SMYD3 结合。虽然需要进行更多研究来确定这些相互作用背后的功能机制及其重要性，但涉及表观遗传癌症标志通路的两种新型 SMYD3 相互作用因子的鉴定为 SMYD3 如何发挥其致癌作用的谜团增添了重要部分。© 2023 作者。

SMDY3 is a histone-lysine N-methyltransferase involved in several oncogenic processes and is believed to play a major role in various cancer hallmarks. Recently, we identified ATM, BRCA2, CHK2, MTOR, BLM, MET, AMPK, and p130 as direct SMYD3 interactors by taking advantage of a library of rare tripeptides, which we first tested for their in vitro binding affinity to SMYD3 and then used as in silico probes to systematically search the human proteome. Here, we used this innovative approach to identify further SMYD3-interacting proteins involved in crucial cancer pathways and found that the chromatin remodeling factors EP300 and TRRAP interact directly with SMYD3, thus linking SMYD3 to the emerging 'nonmutational epigenetic reprogramming' cancer hallmark. Of note, we validated these interactions in gastrointestinal cancer cell lines, including HCT-116 cells, which harbor a C-terminal truncating mutation in EP300, suggesting that EP300 binds to SMYD3 via its N-terminal region. While additional studies are required to ascertain the functional mechanisms underlying these interactions and their significance, the identification of two novel SMYD3 interactors involved in epigenetic cancer hallmark pathways adds important pieces to the puzzle of how SMYD3 exerts its oncogenic role.© 2023 The Authors.