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TRIM37 controls cancer-specific vulnerability to PLK4 inhibition
Centrosomes catalyze microtubule formation for mitotic spindle assembly(1). Centrosomes duplicate once per cell cycle in a process controlled the kinase PLK4(2,3). Following chemical PLK4 inhibition, cell division in the absence of centrosome duplication generates centrosome-less cells that exhibit...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501188/ https://www.ncbi.nlm.nih.gov/pubmed/32908304 http://dx.doi.org/10.1038/s41586-020-2710-1 |
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author | Meitinger, Franz Ohta, Midori Lee, Kian-Yong Watanabe, Sadanori Davis, Robert L. Anzola, John V. Kabeche, Ruth Jenkins, David Shiau, Andrew K. Desai, Arshad Oegema, Karen |
author_facet | Meitinger, Franz Ohta, Midori Lee, Kian-Yong Watanabe, Sadanori Davis, Robert L. Anzola, John V. Kabeche, Ruth Jenkins, David Shiau, Andrew K. Desai, Arshad Oegema, Karen |
author_sort | Meitinger, Franz |
collection | PubMed |
description | Centrosomes catalyze microtubule formation for mitotic spindle assembly(1). Centrosomes duplicate once per cell cycle in a process controlled the kinase PLK4(2,3). Following chemical PLK4 inhibition, cell division in the absence of centrosome duplication generates centrosome-less cells that exhibit delayed, acentrosomal spindle assembly(4). Whether PLK4 inhibitors can be leveraged for cancer treatment 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 accelerates acentrosomal spindle assembly and improves proliferation following PLK4 inhibition, whereas high TRIM37 inhibits 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), which renders these cancer types highly sensitive to PLK4 inhibition. TRIM37 inactivation improves acentrosomal mitosis because TRIM37 prevents PLK4 self-assembly into centrosome-independent condensates that serve as ectopic microtubule-organizing centers. By contrast, elevated TRIM37 expression inhibits acentrosomal spindle assembly via a distinct mechanism that involves degradation of the centrosomal component CEP192. Thus, TRIM37 is a critical 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. |
format | Online Article Text |
id | pubmed-7501188 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
record_format | MEDLINE/PubMed |
spelling | pubmed-75011882021-03-09 TRIM37 controls cancer-specific vulnerability to PLK4 inhibition Meitinger, Franz Ohta, Midori Lee, Kian-Yong Watanabe, Sadanori Davis, Robert L. Anzola, John V. Kabeche, Ruth Jenkins, David Shiau, Andrew K. Desai, Arshad Oegema, Karen Nature Article Centrosomes catalyze microtubule formation for mitotic spindle assembly(1). Centrosomes duplicate once per cell cycle in a process controlled the kinase PLK4(2,3). Following chemical PLK4 inhibition, cell division in the absence of centrosome duplication generates centrosome-less cells that exhibit delayed, acentrosomal spindle assembly(4). Whether PLK4 inhibitors can be leveraged for cancer treatment 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 accelerates acentrosomal spindle assembly and improves proliferation following PLK4 inhibition, whereas high TRIM37 inhibits 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), which renders these cancer types highly sensitive to PLK4 inhibition. TRIM37 inactivation improves acentrosomal mitosis because TRIM37 prevents PLK4 self-assembly into centrosome-independent condensates that serve as ectopic microtubule-organizing centers. By contrast, elevated TRIM37 expression inhibits acentrosomal spindle assembly via a distinct mechanism that involves degradation of the centrosomal component CEP192. Thus, TRIM37 is a critical 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. 2020-09-09 2020-09 /pmc/articles/PMC7501188/ /pubmed/32908304 http://dx.doi.org/10.1038/s41586-020-2710-1 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Meitinger, Franz Ohta, Midori Lee, Kian-Yong Watanabe, Sadanori Davis, Robert L. Anzola, John V. Kabeche, Ruth Jenkins, David Shiau, Andrew K. Desai, Arshad Oegema, Karen TRIM37 controls cancer-specific vulnerability to PLK4 inhibition |
title | TRIM37 controls cancer-specific vulnerability to PLK4 inhibition |
title_full | TRIM37 controls cancer-specific vulnerability to PLK4 inhibition |
title_fullStr | TRIM37 controls cancer-specific vulnerability to PLK4 inhibition |
title_full_unstemmed | TRIM37 controls cancer-specific vulnerability to PLK4 inhibition |
title_short | TRIM37 controls cancer-specific vulnerability to PLK4 inhibition |
title_sort | trim37 controls cancer-specific vulnerability to plk4 inhibition |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501188/ https://www.ncbi.nlm.nih.gov/pubmed/32908304 http://dx.doi.org/10.1038/s41586-020-2710-1 |
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