Simon Clara, Stielow Bastian, Nist Andrea, Rohner Iris, Weber Lisa Marie, Geller Merle, Fischer Sabrina, Stiewe Thorsten, Liefke Robert
Institute of Molecular Biology and Tumor Research (IMT), Faculty of Medicine, Philipps University of Marburg, 35043 Marburg, Germany.
Genomics Core Facility, Faculty of Medicine, Institute of Molecular Oncology, Member of the German Center for Lung Research (DZL), Philipps University of Marburg, 35043 Marburg, Germany.
Biology (Basel). 2022 Apr 6;11(4):557. doi: 10.3390/biology11040557.
The unmethylated CpG island-binding protein SAMD1 is upregulated in many human cancer types, but its cancer-related role has not yet been investigated. Here, we used the hepatocellular carcinoma cell line HepG2 as a cancer model and investigated the cellular and transcriptional roles of SAMD1 using ChIP-Seq and RNA-Seq. SAMD1 targets several thousand gene promoters, where it acts predominantly as a transcriptional repressor. HepG2 cells with SAMD1 deletion showed slightly reduced proliferation, but strongly impaired clonogenicity. This phenotype was accompanied by the decreased expression of pro-proliferative genes, including MYC target genes. Consistently, we observed a decrease in the active H3K4me2 histone mark at most promoters, irrespective of SAMD1 binding. Conversely, we noticed an increase in interferon response pathways and a gain of H3K4me2 at a subset of enhancers that were enriched for IFN-stimulated response elements (ISREs). We identified key transcription factor genes, such as , , and , that were directly repressed by SAMD1. Moreover, SAMD1 deletion also led to the derepression of the PI3K-inhibitor , contributing to diminished mTOR signaling and ribosome biogenesis pathways. Our work suggests that SAMD1 is involved in establishing a pro-proliferative setting in hepatocellular carcinoma cells. Inhibiting SAMD1's function in liver cancer cells may therefore lead to a more favorable gene signature.
未甲基化的CpG岛结合蛋白SAMD1在多种人类癌症类型中上调，但其与癌症相关的作用尚未得到研究。在此，我们使用肝癌细胞系HepG2作为癌症模型，并通过染色质免疫沉淀测序（ChIP-Seq）和RNA测序（RNA-Seq）研究了SAMD1的细胞和转录作用。SAMD1靶向数千个基因启动子，在这些启动子处它主要作为转录抑制因子发挥作用。缺失SAMD1的HepG2细胞增殖略有降低，但克隆形成能力严重受损。这种表型伴随着促增殖基因（包括MYC靶基因）表达的降低。一致地，我们观察到大多数启动子处活性组蛋白H3K4me2标记减少，与SAMD1的结合无关。相反，我们注意到干扰素反应途径增加，并且在富含干扰素刺激反应元件（ISRE）的一部分增强子处H3K4me2增加。我们鉴定了被SAMD1直接抑制的关键转录因子基因，如 、 和 。此外，SAMD1的缺失还导致PI3K抑制剂 的去抑制，导致mTOR信号传导和核糖体生物发生途径减弱。我们的工作表明SAMD1参与在肝癌细胞中建立促增殖环境。因此，抑制SAMD1在肝癌细胞中的功能可能导致更有利的基因特征。
