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SAMD1 抑制胰腺导管腺癌中的上皮-间充质转化途径。

SAMD1 suppresses epithelial-mesenchymal transition pathways in pancreatic ductal adenocarcinoma.

机构信息

Institute of Molecular Biology and Tumor Research (IMT), Philipps University of Marburg, Marburg, Germany.

Protein Analysis Unit, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-University (LMU) Munich, Martinsried, Germany.

出版信息

PLoS Biol. 2024 Aug 13;22(8):e3002739. doi: 10.1371/journal.pbio.3002739. eCollection 2024 Aug.

DOI:10.1371/journal.pbio.3002739
PMID:39137238
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11343471/
Abstract

Pancreatic ductal adenocarcinoma (PDAC) poses a significant threat due to its tendency to evade early detection, frequent metastasis, and the subsequent challenges in devising effective treatments. Processes that govern epithelial-mesenchymal transition (EMT) in PDAC hold promise for advancing novel therapeutic strategies. SAMD1 (SAM domain-containing protein 1) is a CpG island-binding protein that plays a pivotal role in the repression of its target genes. Here, we revealed that SAMD1 acts as a repressor of genes associated with EMT. Upon deletion of SAMD1 in PDAC cells, we observed significantly increased migration rates. SAMD1 exerts its effects by binding to specific genomic targets, including CDH2, encoding N-cadherin, which emerged as a driver of enhanced migration upon SAMD1 knockout. Furthermore, we discovered the FBXO11-containing E3 ubiquitin ligase complex as an interactor and negative regulator of SAMD1, which inhibits SAMD1 chromatin-binding genome-wide. High FBXO11 expression in PDAC is associated with poor prognosis and increased expression of EMT-related genes, underlining an antagonistic relationship between SAMD1 and FBXO11. In summary, our findings provide insights into the regulation of EMT-related genes in PDAC, shedding light on the intricate role of SAMD1 and its interplay with FBXO11 in this cancer type.

摘要

胰腺导管腺癌 (PDAC) 具有逃避早期检测、频繁转移的倾向，且后续治疗效果不佳，因此构成了重大威胁。调控 PDAC 上皮间质转化 (EMT) 的过程有望为开发新的治疗策略提供帮助。SAMD1（含 SAM 结构域蛋白 1）是一种 CpG 岛结合蛋白，在抑制其靶基因方面发挥着关键作用。本研究揭示 SAMD1 可作为 EMT 相关基因的抑制因子。在 PDAC 细胞中敲除 SAMD1 后，观察到迁移率显著增加。SAMD1 通过与特定的基因组靶点结合发挥作用，其中包括编码 N-钙黏蛋白的 CDH2，SAMD1 敲除后 CDH2 成为促进迁移的驱动基因。此外，我们发现 FBXO11 包含的 E3 泛素连接酶复合物是 SAMD1 的相互作用因子和负调控因子，可抑制 SAMD1 在全基因组范围内的染色质结合。在 PDAC 中，FBXO11 高表达与预后不良和 EMT 相关基因表达增加相关，这表明 SAMD1 和 FBXO11 之间存在拮抗关系。综上所述，本研究结果为调控 PDAC 中 EMT 相关基因提供了新见解，阐明了 SAMD1 的复杂作用及其与 FBXO11 在该癌症类型中的相互作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2cd/11343471/c49d8f774ff7/pbio.3002739.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2cd/11343471/a73c0bb262aa/pbio.3002739.g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2cd/11343471/c49d8f774ff7/pbio.3002739.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2cd/11343471/a73c0bb262aa/pbio.3002739.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2cd/11343471/09495b6442aa/pbio.3002739.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2cd/11343471/faba53258137/pbio.3002739.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2cd/11343471/a36d70292797/pbio.3002739.g004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2cd/11343471/c49d8f774ff7/pbio.3002739.g006.jpg

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