TUG1

来自日本名古屋大学等机构的科学家们通过研究揭开了癌细胞如何应对复制压力与牛磺酸上调基因1（TUG1, Taurine Upregulated Gene 1）之间的关联关联。 癌基因诱导的DNA复制压力（RS）和随后的致病性R-环形成会阻碍癌细胞S期的进展，尽管如此，癌细胞仍然能在如此高压力的环境中继续增殖，其背后的机制目前研究人员并不清楚。近日，一篇发表在国际杂志Nature Communications上题为“TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation”的研究报告中，来自日本名古屋大学等机构的科学家们通过研究揭开了癌细胞如何应对复制压力与牛磺酸上调基因1（TUG1, Taurine Upregulated Gene 1）之间的关联关联，通过利用药物来靶向作用TUG1，研究人员就能控制小鼠机体的脑瘤生长，这或许就有望帮助开发一种新型潜在的疗法来抵御诸如胶质母细胞瘤等人类恶性脑瘤。 研究者Yutaka Suzuki教授说道，这些研究结果有望转化为潜在的治疗应用，因为TUG1在胶质母细胞瘤中会高度表达；这项研究中，研究人员成功开发出了一种名为TUG1-DDS的治疗性药物，其能选择性地靶向作用TUG1；尤其当与替莫唑胺（temozolomide）标准疗法联合使用时还能明显抑制肿瘤的生长并改善宿主生存情况，因此，其或许能作为一种治疗胶质母细胞瘤的潜在有效药物。 为了理解TUG1如何潜在治疗最危险形式的脑癌，理解癌症如何促使宿主细胞的常规过程来对抗自己从而产生一种有利于癌细胞生长的环境或许是非常重要的，即使是诸如复制等基本的细胞过程也能被癌症有效利用。当细胞分裂时，其会复制自己的DNA，这样细胞就有了完整的遗传信息，双链DNA能被解开并分类成两条单链，每一条单链都能作为模版通过结合RNA来产生两个相同的副本，一种称之为R-环的DNA:RNA杂交结构或许有助于解开DNA链，并在DNA双链解开时帮其稳定。 通过靶向作用控制DNA复制压力的关键基因或有望治疗人类脑癌。 图片来源：Nature Communications (2023). DOI:10.1038/s41467-023-40243-8 为了改善癌细胞的生存状况，侵袭性的细胞能阻碍DNA复制的天然过程，细胞会诱导复制压力（RS），从而导致DNA链断裂以及不配对的DNA单链的增加，其结果就会导致基因组的不稳定从而促进肿瘤生长。癌细胞中存在一种非常狡猾的平衡行为，因为增加的活性可能会适得其反，复制压力和R-环的积累会引起癌细胞死亡，为了调节基因组，癌细胞就会转向长非编码RNAs（lncRNAs），从而就会允许其修复自身的DNA损伤并移除不需要的R-环结构。这项研究中，研究人员识别出了lncRNA TUG1的关键作用，他们发现，TUG1能与两种蛋白（DHX9和RPA32）共同抑制潜在有害的R-环结构；因此，TUG1-RPA-DHX9的相互作用或许就是调节已知易受DNA损伤和突变影响的区域R-环结构的不可或缺的机制。 研究者Kondo还表示，我们发现，TUG1能快速被上调以应对复制压力，当降低癌细胞中TUG1的表达时就会出现严重的DNA损伤和细胞死亡，因此看到TUG1表达的快速上升从而应对复制压力让研究人员非常兴奋。正常情况下，蛋白质对刺激产生反应从而增加表达量需要几个小时甚至更长时间，但RNA能被快速合成，TUG1是一种特殊的RNA分子，其会快速增加以应对复制压力，这就表明其非常有必要对危及情况快速做出反应。相关研究发现或为其它癌症疗法的开发能提供一定的希望，研究者解释道，TUG1抑制剂也被发现能在其它类型癌症的治疗中有效，比如胰腺癌和卵巢癌等，因此，名为TUG1-DDS的新型疗法或能有效治疗TUG1表达的其它癌症类型。 综上，本文研究揭示了TUG1或能作为一种对于解决R-环在癌细胞中积累的重要分子机的关键角色，同时表明靶向作用TUG1或许有望帮助开发治疗癌症的潜在治疗性手段。（生物谷Bioon.com） 原始出处： Suzuki, M.M., Iijima, K., Ogami, K. et al. TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation. Nat Commun 14, 4521 (2023). doi：10.1038/s41467-023-40243-8

A new study has revealed a crucial link between the TUG1 gene and the ability of cancer cells to proliferate under high-stress conditions. Targeting this gene with a new therapy suppressed tumor growth and found increased chances of survival. These findings suggest a novel way to fight aggressive brain tumors. A new study has unravelled a crucial link between how cancer cells cope with replication stress and the role of Taurine Upregulated Gene 1 (TUG1). By targeting TUG1 with a drug, the researchers were able to control brain tumor growth in mice, suggesting a potential strategy to combat aggressive brain tumors such as glioblastomas. "These findings have the potential to be translated into therapeutic applications, as TUG1 is highly expressed in glioblastoma," said lead researcher Professor Yutaka Suzuki. "In this study, we successfully developed a therapeutic drug named TUG1-DDS, which selectively targets TUG1. It significantly suppressed tumor growth and improved survival, especially when administered in combination with the standard treatment of temozolomide. Therefore, it is a potentially effective therapeutic agent for treating glioblastoma." To understand how TUG1 could potentially treat the most dangerous forms of brain cancer, it is important to understand how cancer turns the usual processes of host cells against themselves to create an environment favorable to cancer cell growth. Even essential cell processes, such as replication, are used to the cancer's advantage. When a cell divides, it replicates its DNA, so that both cells have a full complement of hereditary information. The double-stranded DNA is unwound and separated into two single strands that each serve as a template for creating two identical copies by combining with RNA. A DNA:RNA hybrid structure called an R-loop helps unwind the DNA and stabilizes it as it is unwound. To improve the conditions for cancer cells, the invasive cells hinder the natural process of DNA replication. The cells induce replication stress (RS), which results in the DNA strands breaking and unpaired single strands of DNA increasing. The result is an instability in the genome that favors tumor growth. Cancer cells have a tricky balancing act because the increased activity can potentially backfire. RS and R-loop accumulation can also cause cancer cell death. To regulate the genome, cancer cells turn to long noncoding RNAs (lncRNAs), which allow them to repair their own DNA damage and remove unwanted R-loops. In a new study, led by Yutaka Kondo and Miho Suzuki at Nagoya University Graduate School of Medicine, the investigators identified the role of the lncRNA TUG1. They found that TUG1 suppresses the potentially harmful R-loops together with two proteins, DHX9 and RPA32. Taken together, the TUG1-RPA-DHX9 interaction is an indispensable mechanism for regulating R-loops in regions that are known to be susceptible to DNA damage and mutations. Their findings were published in Nature Communications. Kondo and Suzuki also found that TUG1 was rapidly up-regulated in response to RS. When they reduced TUG1 expression in cancer cells, they found severe DNA damage and cell death. "It was exciting to see the rapid increase in expression of TUG1 in response to replication stress," said Dr. Suzuki. She continues: "Normally, it takes several hours or more for proteins to increase in response to stimuli, but RNA can be synthesized rapidly. That TUG1, an RNA molecule, increases immediately in response to replication stress indicates that it is necessary to respond quickly to critical situations." These findings offer hope for the development of treatment for other cancers. As Dr. Kondo explains: "TUG1 inhibitors have also been found to be effective in other types of cancer, such as pancreatic cancer and ovarian cancer. Therefore, our novel treatment, TUG1-DDS, could also be effective in other cancer types with expression of TUG1."