Song Haoyun, Guo Zhao, Xie Kun, Liu Xiangwen, Yang Xuguang, Shen Rong, Wang Degui
School of Basic Medical Sciences, Lanzhou University, Gansu, China.
NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Lanzhou, Gansu Province, China.
Cell Prolif. 2025 Feb;58(2):e13759. doi: 10.1111/cpr.13759. Epub 2024 Oct 30.
Breast cancer is associated with high morbidity and mortality, which are closely influenced by protein post-translational modifications (PTMs). Lysine crotonylation (Kcr) serves as a newly identified PTM type that plays a role in various biological processes; however, its involvement in breast cancer progression remains unclear. Minichromosome maintenance 6 (MCM6) is a critical component of DNA replication and has been previous confirmed to exhibit a significant role in tumorigenesis. Despite this, a comprehensive analysis of MCM6, particularly regarding its modifications in breast cancer is lacking. In this study, we found MCM6 is upregulated in breast invasive carcinoma (BRCA) and is associated with poorer overall survival by regulating the DNA damage repair mechanisms. Furthermore, MCM6-knockdown resulted in decreased cell proliferation and inhibited the DNA replication, leading to DNA replication stress and sustained DNA damage, thereby enhancing the chemotherapeutic sensitivity of breast cancer. Additionally, SIRT7-mediated crotonylation of MCM6 at K599 (MCM6-K599cr) was significantly upregulated in response to DNA replication stress, primarily due to the disassemebly of the MCM2-7 complex and regulated by RNF8-mediated ubiquitination. Concurrently, kaempferol, which acts as a regulator of SIRT7, was found to enhance the Kcr level of MCM6, reducing tumour weight, particular when combined with paclitaxel, highlighting its potential chemotherapeutic target for BRCA therapy.
乳腺癌具有高发病率和高死亡率，蛋白质翻译后修饰（PTM）对其有密切影响。赖氨酸巴豆酰化（Kcr）是一种新发现的PTM类型，在多种生物学过程中发挥作用；然而，其在乳腺癌进展中的作用仍不清楚。微小染色体维持蛋白6（MCM6）是DNA复制的关键组成部分，此前已证实其在肿瘤发生中发挥重要作用。尽管如此，目前缺乏对MCM6的全面分析，尤其是关于其在乳腺癌中的修饰情况。在本研究中，我们发现MCM6在乳腺浸润性癌（BRCA）中上调，并通过调节DNA损伤修复机制与较差的总生存期相关。此外，敲低MCM6导致细胞增殖减少并抑制DNA复制，导致DNA复制应激和持续性DNA损伤，从而增强乳腺癌的化疗敏感性。此外，SIRT7介导的MCM6在K599位点的巴豆酰化（MCM6-K599cr）在DNA复制应激反应中显著上调，主要是由于MCM2-7复合物的解离，并受RNF8介导的泛素化调控。同时，发现作为SIRT7调节剂的山奈酚可提高MCM6的Kcr水平，减轻肿瘤重量，尤其是与紫杉醇联合使用时，突出了其作为BRCA治疗潜在化疗靶点的作用。
