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TRIM37 controls cancer-specific vulnerability to PLK4 inhibition
Nature ( IF 64.8 ) Pub Date : 2020-09-09 , DOI: 10.1038/s41586-020-2710-1
Franz Meitinger 1 , Midori Ohta 1 , Kian-Yong Lee 1 , Sadanori Watanabe 1 , Robert L Davis 2 , John V Anzola 2 , Ruth Kabeche 1 , David A Jenkins 2 , Andrew K Shiau 2, 3 , Arshad Desai 1, 3, 4 , Karen Oegema 1, 3, 4
Affiliation  

Centrosomes catalyse the formation of microtubules needed to assemble the mitotic spindle apparatus 1 . 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 assembly 4 . 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 cancer 5 – 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. Acentrosomal assembly of the mitotic spindle upon inhibition of the PLK4 protein is shown to depend on the ubiquitin ligase TRIM37, with implications for the use of PLK4 inhibitors to treat neuroblastoma and breast cancer.

中文翻译:

TRIM37 控制癌症对 PLK4 抑制的特异性脆弱性

中心体催化组装有丝分裂纺锤体装置 1 所需的微管的形成。在由丝氨酸/苏氨酸蛋白激酶 PLK4 控制的过程中,中心体本身在每个细胞周期复制一次(参考文献 2、3)。当 PLK4 被化学抑制时,细胞分裂进行而没有中心体重复,产生无中心体的细胞,这些细胞表现出延迟的中心体纺锤体组装 4。PLK4 抑制剂是否可用于治疗癌症尚不清楚。在这里,我们表明 PLK4 抑制后的中心体纺锤体组装取决于中心体泛素连接酶 TRIM37 的水平。低TRIM37水平在PLK4抑制后加速中心体纺锤体组装并改善增殖,而高TRIM37水平抑制中心体纺锤体组装,导致有丝分裂失败和增殖停止。含有 TRIM37 基因的 Chr17q 区域经常在神经母细胞瘤和乳腺癌中扩增 5-8 ,使这些癌症类型对 PLK4 抑制高度敏感。我们发现,TRIM37 失活可改善中心体有丝分裂,因为 TRIM37 阻止 PLK4 自组装成作为异位微管组织中心的中心体独立凝聚物。相比之下,TRIM37 表达升高通过一种独特的机制抑制中心体纺锤体组装,该机制涉及中心体成分 CEP192 的降解。因此,TRIM37 是 PLK4 抑制有丝分裂易感性的重要决定因素。TRIM37 与普遍的癌症相关基因组变化的联系——包括神经母细胞瘤中的 17q 增益和乳腺癌中的 17q23 扩增——可能为使用 PLK4 抑制触发选择性有丝分裂失败提供机会,并为这些癌症的治疗提供新途径。抑制 PLK4 蛋白后有丝分裂纺锤体的中心体组装显示依赖于泛素连接酶 TRIM37,这对使用 PLK4 抑制剂治疗神经母细胞瘤和乳腺癌有影响。
更新日期:2020-09-09
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