小柯机器人

TRIM37控制肿瘤中PLK4抑制的易感性
2020-09-12 21:39

美国路德维希癌症研究所Karen Oegema、Arshad Desai以及Franz Meitinger研究组合作取得最新进展。他们发现TRIM37控制肿瘤特异的对PLK4抑制的易感性。相关论文于2020年9月9日发表在《自然》杂志上。

他们显示PLK4抑制后的无中心体纺锤体组装取决于中心体泛素连接酶TRIM37的水平。TRIM37的水平低会加速中心纺锤体的组装并促进PLK4抑制后的增殖,而高水平TRIM37会抑制无中心体纺锤体组装,从而导致有丝分裂失败和增殖停止。含有TRIM37基因的Chr17q区在神经母细胞瘤和乳腺癌中经常被扩增,从而使这些癌症类型对PLK4抑制高度敏感。

他们发现TRIM37失活促进了人染色体上的有丝分裂,因为TRIM37阻止了PLK4自组装成不依赖于中心体的凝聚体,这些凝聚体充当了异位微管组织中心。相比之下,提高的TRIM37表达通过涉及中心体成分CEP192降解的独特机制,抑制了无中心体纺锤体组装。

因此,TRIM37是抑制PLK4的有丝分裂易感性的重要决定因素。TRIM37与普遍存在的癌症相关基因组变化的联系(包括神经母细胞瘤中17q的增加和乳腺癌中17q23的扩增),可能提供PLK4抑制来触发选择性有丝分裂失败的机会,并为这些癌症的治疗提供新途径。

研究人员表示,中心体催化微管形成,需要有丝分裂纺锤体机器组装。在丝氨酸/苏氨酸蛋白激酶PLK4控制的过程中,中心体自身每个细胞周期复制一次。当PLK4被化学抑制后,细胞分裂将继续进行,而无中心体复制,从而产生无中心体的细胞,这些细胞显示出延迟的中心体纺锤体组装。尚不清楚PLK4抑制剂是否可用于治疗癌症。

附:英文原文

Title: TRIM37 controls cancer-specific vulnerability to PLK4 inhibition

Author: Franz Meitinger, Midori Ohta, Kian-Yong Lee, Sadanori Watanabe, Robert L. Davis, John V. Anzola, Ruth Kabeche, David A. Jenkins, Andrew K. Shiau, Arshad Desai, Karen Oegema

Issue&Volume: 2020-09-09

Abstract: Centrosomes catalyse the formation of microtubules needed to assemble the mitotic spindle apparatus1. Centrosomes themselves duplicate once per cell cycle, in a process that is controlled by the serine/threonine protein kinase PLK4 (refs. 2,3). When PLK4 is chemically inhibited, cell division proceeds without centrosome duplication, generating centrosome-less cells that exhibit delayed, acentrosomal spindle assembly4. Whether PLK4 inhibitors can be leveraged as a treatment for cancer is not yet clear. Here we show that acentrosomal spindle assembly following PLK4 inhibition depends on levels of the centrosomal ubiquitin ligase TRIM37. Low TRIM37 levels accelerate acentrosomal spindle assembly and improve proliferation following PLK4 inhibition, whereas high TRIM37 levels inhibit acentrosomal spindle assembly, leading to mitotic failure and cessation of proliferation. The Chr17q region containing the TRIM37 gene is frequently amplified in neuroblastoma and in breast cancer5,6,7,8, rendering these cancer types highly sensitive to PLK4 inhibition. We find that inactivating TRIM37 improves acentrosomal mitosis because TRIM37 prevents PLK4 from self-assembling into centrosome-independent condensates that serve as ectopic microtubule-organizing centres. By contrast, elevated TRIM37 expression inhibits acentrosomal spindle assembly through a distinct mechanism that involves degradation of the centrosomal component CEP192. Thus, TRIM37 is an essential determinant of mitotic vulnerability to PLK4 inhibition. Linkage of TRIM37 to prevalent cancer-associated genomic changes—including 17q gain in neuroblastoma and 17q23 amplification in breast cancer—may offer an opportunity to use PLK4 inhibition to trigger selective mitotic failure and provide new avenues to treatments for these cancers.

DOI: 10.1038/s41586-020-2710-1

Source: https://www.nature.com/articles/s41586-020-2710-1

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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