MELK expression correlates with tumor mitotic activity but is not required for cancer growth
The Maternal Embryonic Leucine Zipper Kinase (MELK) has been identified as a promising therapeutic target in multiple cancer types. MELK over-expression is associated with aggressive disease, and MELK has been implicated in numerous cancer-related processes, including chemotherapy resistance, stem c...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-02-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/32838 |
| _version_ | 1828382999491641344 |
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| author | Christopher J Giuliano Ann Lin Joan C Smith Ann C Palladino Jason M Sheltzer |
| author_facet | Christopher J Giuliano Ann Lin Joan C Smith Ann C Palladino Jason M Sheltzer |
| author_sort | Christopher J Giuliano |
| collection | DOAJ |
| description | The Maternal Embryonic Leucine Zipper Kinase (MELK) has been identified as a promising therapeutic target in multiple cancer types. MELK over-expression is associated with aggressive disease, and MELK has been implicated in numerous cancer-related processes, including chemotherapy resistance, stem cell renewal, and tumor growth. Previously, we established that triple-negative breast cancer cell lines harboring CRISPR/Cas9-induced null mutations in MELK proliferate at wild-type levels in vitro (Lin et al., 2017). Here, we generate several additional knockout clones of MELK and demonstrate that across cancer types, cells lacking MELK exhibit wild-type growth in vitro, under environmental stress, in the presence of cytotoxic chemotherapies, and in vivo. By combining our MELK-knockout clones with a recently described, highly specific MELK inhibitor, we further demonstrate that the acute inhibition of MELK results in no specific anti-proliferative phenotype. Analysis of gene expression data from cohorts of cancer patients identifies MELK expression as a correlate of tumor mitotic activity, explaining its association with poor clinical prognosis. In total, our results demonstrate the power of CRISPR/Cas9-based genetic approaches to investigate cancer drug targets, and call into question the rationale for treating patients with anti-MELK monotherapies. |
| first_indexed | 2024-12-10T04:41:55Z |
| format | Article |
| id | doaj.art-74b1625563b9473ca17e33fb23458412 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T04:41:55Z |
| publishDate | 2018-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-74b1625563b9473ca17e33fb234584122022-12-22T02:01:52ZengeLife Sciences Publications LtdeLife2050-084X2018-02-01710.7554/eLife.32838MELK expression correlates with tumor mitotic activity but is not required for cancer growthChristopher J Giuliano0https://orcid.org/0000-0002-0586-6095Ann Lin1Joan C Smith2Ann C Palladino3Jason M Sheltzer4https://orcid.org/0000-0003-1381-1323Cold Spring Harbor Laboratory, Cold Spring Harbor, United StatesCold Spring Harbor Laboratory, Cold Spring Harbor, United StatesGoogle, Inc., New York, United StatesCold Spring Harbor Laboratory, Cold Spring Harbor, United StatesCold Spring Harbor Laboratory, Cold Spring Harbor, United StatesThe Maternal Embryonic Leucine Zipper Kinase (MELK) has been identified as a promising therapeutic target in multiple cancer types. MELK over-expression is associated with aggressive disease, and MELK has been implicated in numerous cancer-related processes, including chemotherapy resistance, stem cell renewal, and tumor growth. Previously, we established that triple-negative breast cancer cell lines harboring CRISPR/Cas9-induced null mutations in MELK proliferate at wild-type levels in vitro (Lin et al., 2017). Here, we generate several additional knockout clones of MELK and demonstrate that across cancer types, cells lacking MELK exhibit wild-type growth in vitro, under environmental stress, in the presence of cytotoxic chemotherapies, and in vivo. By combining our MELK-knockout clones with a recently described, highly specific MELK inhibitor, we further demonstrate that the acute inhibition of MELK results in no specific anti-proliferative phenotype. Analysis of gene expression data from cohorts of cancer patients identifies MELK expression as a correlate of tumor mitotic activity, explaining its association with poor clinical prognosis. In total, our results demonstrate the power of CRISPR/Cas9-based genetic approaches to investigate cancer drug targets, and call into question the rationale for treating patients with anti-MELK monotherapies.https://elifesciences.org/articles/32838CRISPR/Cas9drug targetsmitotic kinasecell cyclebiomarkers |
| spellingShingle | Christopher J Giuliano Ann Lin Joan C Smith Ann C Palladino Jason M Sheltzer MELK expression correlates with tumor mitotic activity but is not required for cancer growth eLife CRISPR/Cas9 drug targets mitotic kinase cell cycle biomarkers |
| title | MELK expression correlates with tumor mitotic activity but is not required for cancer growth |
| title_full | MELK expression correlates with tumor mitotic activity but is not required for cancer growth |
| title_fullStr | MELK expression correlates with tumor mitotic activity but is not required for cancer growth |
| title_full_unstemmed | MELK expression correlates with tumor mitotic activity but is not required for cancer growth |
| title_short | MELK expression correlates with tumor mitotic activity but is not required for cancer growth |
| title_sort | melk expression correlates with tumor mitotic activity but is not required for cancer growth |
| topic | CRISPR/Cas9 drug targets mitotic kinase cell cycle biomarkers |
| url | https://elifesciences.org/articles/32838 |
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