TRIM37控制腫瘤中PLK4抑制的易感性
作者：
小柯機器人發布時間：2020/9/12 21:39:20
美國路德維希癌症研究所Karen Oegema、Arshad Desai以及Franz Meitinger研究組合作取得最新進展。他們發現TRIM37控制腫瘤特異的對PLK4抑制的易感性。相關論文於2020年9月9日發表在《自然》雜誌上。
他們顯示PLK4抑制後的無中心體紡錘體組裝取決於中心體泛素連接酶TRIM37的水平。TRIM37的水平低會加速中心紡錘體的組裝並促進PLK4抑制後的增殖，而高水平TRIM37會抑制無中心體紡錘體組裝，從而導致有絲分裂失敗和增殖停止。含有TRIM37基因的Chr17q區在神經母細胞瘤和乳腺癌中經常被擴增，從而使這些癌症類型對PLK4抑制高度敏感。
他們發現TRIM37失活促進了人染色體上的有絲分裂，因為TRIM37阻止了PLK4自組裝成不依賴於中心體的凝聚體，這些凝聚體充當了異位微管組織中心。相比之下，提高的TRIM37表達通過涉及中心體成分CEP192降解的獨特機制，抑制了無中心體紡錘體組裝。
因此，TRIM37是抑制PLK4的有絲分裂易感性的重要決定因素。TRIM37與普遍存在的癌症相關基因組變化的聯繫（包括神經母細胞瘤中17q的增加和乳腺癌中17q23的擴增），可能提供PLK4抑制來觸發選擇性有絲分裂失敗的機會，並為這些癌症的治療提供新途徑。
研究人員表示，中心體催化微管形成，需要有絲分裂紡錘體機器組裝。在絲氨酸/蘇氨酸蛋白激酶PLK4控制的過程中，中心體自身每個細胞周期複製一次。當PLK4被化學抑制後，細胞分裂將繼續進行，而無中心體複製，從而產生無中心體的細胞，這些細胞顯示出延遲的中心體紡錘體組裝。尚不清楚PLK4抑制劑是否可用於治療癌症。
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