新型 SMYD3 抑制剂 EM127 会损害对化疗引起的 DNA 损伤的 DNA 修复反应，并逆转癌症化疗耐药性。
The novel SMYD3 inhibitor EM127 impairs DNA repair response to chemotherapy-induced DNA damage and reverses cancer chemoresistance.
发表日期：2024 May 30
作者：
Paola Sanese, Katia De Marco, Martina Lepore Signorile, Francesca La Rocca, Giovanna Forte, Marialaura Latrofa, Candida Fasano, Vittoria Disciglio, Elisabetta Di Nicola, Antonino Pantaleo, Giusy Bianco, Vito Spilotro, Claudia Ferroni, Matilde Tubertini, Nicoletta Labarile, Lucia De Marinis, Raffaele Armentano, Gianluigi Gigante, Valerio Lantone, Giuliano Lantone, Marina Naldi, Manuela Bartolini, Greta Varchi, Alberto Del Rio, Valentina Grossi, Cristiano Simone
来源：
Cellular & Molecular Immunology
摘要：
SMYD3 被发现与癌症进展有关。它的过度表达与癌症的生长和侵袭相关，尤其是在胃肠道肿瘤中。 SMYD3 反式激活多种致癌机制，有利于癌症的发展。此外，最近表明，SMYD3 是通过促进同源重组 (HR) 修复来进行 DNA 修复所必需的。采用细胞和体内模型来研究 SMYD3 在癌症化疗耐药中的作用。对SMYD3-KO细胞、耐药癌细胞系、新辅助治疗后切除的患者残留胃或直肠肿瘤以及小鼠模型进行了分析。此外，新型SMYD3共价抑制剂EM127被用来评估操纵SMYD3活性对癌细胞系、肿瘤球和癌症小鼠模型对化疗药物（CHT）敏感性的影响。在此，我们报道SMYD3介导癌细胞对CHT的敏感性。事实上，缺乏 SMYD3 功能的癌细胞对 CHT 的反应性增强，而恢复其表达则促进了化疗耐药性。具体来说，SMYD3 对于修复 CHT 诱导的双链断裂至关重要，因为它甲基化上游传感器 ATM，并通过 CHK2 和 p53 磷酸化允许 HR 级联传播，从而促进癌细胞存活。使用新型化合物 EM127 抑制 SMYD3 在结直肠癌、胃癌和乳腺癌细胞、肿瘤球和临床前结直肠癌模型中显示出与 CHT 的协同作用。总体而言，我们的结果表明，靶向 SMYD3 可能是克服化疗耐药性的有效治疗策略。© 2024。作者。
SMYD3 has been found implicated in cancer progression. Its overexpression correlates with cancer growth and invasion, especially in gastrointestinal tumors. SMYD3 transactivates multiple oncogenic mechanisms, favoring cancer development. Moreover, it was recently shown that SMYD3 is required for DNA restoration by promoting homologous recombination (HR) repair.In cellulo and in vivo models were employed to investigate the role of SMYD3 in cancer chemoresistance. Analyses of SMYD3-KO cells, drug-resistant cancer cell lines, patients' residual gastric or rectal tumors that were resected after neoadjuvant therapy and mice models were performed. In addition, the novel SMYD3 covalent inhibitor EM127 was used to evaluate the impact of manipulating SMYD3 activity on the sensitization of cancer cell lines, tumorspheres and cancer murine models to chemotherapeutics (CHTs).Here we report that SMYD3 mediates cancer cell sensitivity to CHTs. Indeed, cancer cells lacking SMYD3 functions showed increased responsiveness to CHTs, while restoring its expression promoted chemoresistance. Specifically, SMYD3 is essential for the repair of CHT-induced double-strand breaks as it methylates the upstream sensor ATM and allows HR cascade propagation through CHK2 and p53 phosphorylation, thereby promoting cancer cell survival. SMYD3 inhibition with the novel compound EM127 showed a synergistic effect with CHTs in colorectal, gastric, and breast cancer cells, tumorspheres, and preclinical colorectal cancer models.Overall, our results show that targeting SMYD3 may be an effective therapeutic strategy to overcome chemoresistance.© 2024. The Author(s).