PO.MCB09.03 · 分子与细胞生物学
一种新型一碳通路在癌症中生成核内SAM以进行染色质甲基化
A novel one carbon pathway generates nuclear SAM for chromatin methylation in cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胰腺导管腺癌（PDAC）是最常见且最致命的胰腺癌形式之一，这在很大程度上归因于肝转移和缺乏有效的靶向治疗1,4。比较原发和转移癌灶的新兴证据表明，转移的关键步骤由可逆的表观遗传机制控制，具体为DNA甲基化和组蛋白翻译后修饰（PTM）10,11。这些表观遗传变化与代谢网络紧密相连，后者为这些修饰提供必需的底物和辅因子，从而可能在转移适应中发挥关键作用12。为探究PDAC中代谢与表观遗传之间的这种相互作用，我们利用DepMap数据库来鉴定胰腺癌细胞中的代谢依赖性。我们的无偏分析揭示甲硫氨酸腺苷转移酶2A（MAT2A）为一个特异性脆弱点。MAT2A是一碳代谢（OCM）中的关键酶，OCM是将单碳单元转移至各种底物的通路。至关重要的是，OCM通过生成S-腺苷甲硫氨酸（SAM）——这一通用甲基供体，其可获得性由MAT2A本身严格调控——而成为DNA和组蛋白甲基化过程不可或缺的一部分13。引人注目的是，初步数据揭示MAT2A在转移性肝病灶中具有特异性的核内定位，与其在原发肿瘤中的分布形成对比。此外，对人类肝转移灶的非靶向代谢组学分析显示，大多数一碳代谢（OCM）中间产物（包括SAM）下调，表明转移细胞对这些代谢物有高需求。为模拟这些条件，我们开发了一种类转移培养基（MLM），我们的体外实验证实，在这些条件下MAT2A易位至细胞核、结合染色质，并且是维持组蛋白甲基转移酶（HMT）活性所必需的，从而形成一个此前未被认识的OCM核内网络。靶向MAT2A的核内活性——包括其染色质结合及与染色质相关蛋白的相互作用——可能代表一种针对转移性PDAC的新型治疗策略。此外，本提案旨在阐明一碳代谢影响DNA和组蛋白甲基化模式的具体机制，这是癌症治疗中仍未探索的领域。理解这些潜在机制将有助于鉴定潜在的代谢靶向疗法，以改善PDAC患者的预后。
查看英文原文 English abstract
Pancreatic Ductal Adenocarcinoma (PDAC) stands as the most common and one of the deadliest forms of pancreatic cancer, largely due to liver metastasis and the lack of effective targeted treatments 1,4. Emerging evidence comparing primary and metastatic cancer lesions suggests that key steps of metastasis are controlled by reversible epigenetic mechanisms, specifically DNA methylation and Histone Post Translational Modifications (PTMs) 10,11. These epigenetic changes are intricately linked to metabolic networks, which supply the essential substrates and cofactors for these modifications, thereby potentially playing a crucial role in metastasis adaptation 12. To explore this interplay between metabolism and epigenetics in PDAC, we leveraged the DepMap database to identify metabolic dependencies in pancreatic cancer cells. Our unbiased analysis revealed Methionine Adenosyltransferase 2A (MAT2A) as a specific vulnerability. MAT2A is a key enzyme in the One Carbon Metabolism (OCM), the pathway for transferring single-carbon units to various substrates. Crucially, the OCM is integral to DNA and histone methylation processes by generating S-adenosylmethionine (SAM), the universal methyl donor whose availability is tightly regulated by MAT2A itself 13. Strikingly, preliminary data reveal a specific nuclear localization of MAT2A in metastatic liver lesions, contrasting with its distribution in primary tumors. Additionally, untargeted metabolomic analysis of human liver metastases revealed that most one-carbon metabolism (OCM) intermediates, including SAM, are downregulated, indicating a high demand for these metabolites in metastatic cells. To mimic these conditions, we developed a Metastasis-like Media (MLM), and our in vitro experiments confirmed that under these conditions, MAT2A translocates to the nucleus, binds to chromatin and is required to sustain histone methyltransferases (HMTs) activity, forming a previously unrecognized OCM nuclear network. Targeting the nuclear activity of MAT2A-including its chromatin binding and interactions with chromatin-associated proteins-could represent a novel therapeutic strategy for metastatic PDAC. Furthermore, this proposal seeks to elucidate the specific mechanisms by which one-carbon metabolism influences DNA and histone methylation patterns, an area that remains unexplored in cancer treatment. Understanding these underlying mechanisms will enable the identification of potential metabolism-targeted therapies to improve the prognosis for PDAC patients. <!--EndFragment-->
利益披露 Disclosure
T. Bernasocchi, None.