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TRIM37 controls cancer-specific vulnerability to PLK4 inhibition

机译：Trim37对PLK4抑制控制癌症特异性脆弱性

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摘要

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.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 theTRIM37gene 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 ofTRIM37to 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.
机译：在抑制PLK4蛋白时的含有丝分裂轴的穴位组装依赖于泛素连接酶TRIM37，对使用PLK4抑制剂治疗神经母细胞瘤和乳腺癌的影响。康多莫斯催化组装有丝分子主轴装置所需的微管的形成（1）。在由丝氨酸/苏氨酸蛋白激酶PLK4控制的过程中，以每种细胞周期为中心循环物质一次重复一次（参考文献（2,3））。当PLK4在化学抑制时，细胞分裂在没有中心复制的情况下进行，产生表现出延迟的穴位主轴组件（4）的中心细胞。是否可以将PLK4抑制剂作为癌症的治疗毫无清楚。在这里，我们表明PLK4抑制后的棱腺间主轴组件取决于CentroSomal泛素连接酶TrigPase37的水平。低温37水平加速棱囊组轴组件并改善PLK4抑制后的增殖，而高磨削37水平抑制弓形口轴组件，导致有丝分裂性失效和增殖停止。在神经母细胞瘤和乳腺癌（5-8）中经常扩增含有Schetrim37gene的CHR17Q区域，使这些癌症类型高度敏感的PLK4抑制。我们发现灭活Trim37改善了棱腺细胞瘤病，因为Trim37可防止PLK4自组装成离心体无关的冷凝物，其用作异位微管组织中心。相比之下，升高的TRIM37表达通过涉及CEPROSOMAL组分Cep192的降解的不同机制抑制腺分子主轴组件。因此，TRIM37是对PLK4抑制的有丝分裂脆弱性的基本决定因素。 Trim37的联系到普遍的癌症相关的基因组改变 - 包括神经母细胞瘤的17杆增益和乳腺癌中的17 Q23扩增 - 可以提供使用PLK4抑制来引发选择性有丝分裂失败的机会，并为这些癌症提供新的途径。

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  • 来源
    《Nature》 |2020年第7825期|440-446|共7页
  • 作者

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

  • 作者单位

    Ludwig Inst Canc Res La Jolla CA 92093 USA;

    Ludwig Inst Canc Res La Jolla CA 92093 USA;

    Ludwig Inst Canc Res La Jolla CA 92093 USA;

    Ludwig Inst Canc Res La Jolla CA 92093 USA;

    Ludwig Inst Canc Res Small Mol Discovery Program La Jolla CA USA;

    Ludwig Inst Canc Res Small Mol Discovery Program La Jolla CA USA;

    Ludwig Inst Canc Res La Jolla CA 92093 USA;

    Ludwig Inst Canc Res Small Mol Discovery Program La Jolla CA USA;

    Ludwig Inst Canc Res Small Mol Discovery Program La Jolla CA USA|Univ Calif San Diego Sect Cell & Dev Biol Div Biol Sci La Jolla CA 92093 USA;

    Ludwig Inst Canc Res La Jolla CA 92093 USA|Univ Calif San Diego Sect Cell & Dev Biol Div Biol Sci La Jolla CA 92093 USA|Univ Calif San Diego Dept Cellular & Mol Med La Jolla CA 92093 USA;

    Ludwig Inst Canc Res La Jolla CA 92093 USA|Univ Calif San Diego Sect Cell & Dev Biol Div Biol Sci La Jolla CA 92093 USA|Univ Calif San Diego Dept Cellular & Mol Med La Jolla CA 92093 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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